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Research ArticleNEUROPHARMACOLOGY
Functional Effects of Systemically Administered Agonists and Antagonists of μ, δ, and κ Opioid Receptor Subtypes on Body Temperature in Mice
Alexis K. Baker and Theo F. Meert
Journal of Pharmacology and Experimental Therapeutics September 2002, 302 (3) 1253-1264; DOI: https://doi.org/10.1124/jpet.102.037655
Alexis K. Baker
Theo F. Meert
We have investigated the roles of peripheral and central μ, δ, and κ opioid receptors and their subtypes in opioid-induced hypothermia in mice. Measuring rectal temperature after i.p. injection, opioid agonists [morphine, fentanyl, SNC80 ((+)-4-[(αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)3-methoybenzyl]-N,N-diethylbenzamide), U50,488H ((trans-(dl)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-benzeneacetamide), and loperamide)] were tested alone or with opioid antagonists [naloxone, β-funaltrexamine, naloxonazine, naltrindole, 7-benzylidenenaltrexone (BNTX), naltriben, nor-binaltorphimine, 2-(3,4-dichlorophenyl)-N-methyl-N-[(1S)-1-(3-isothiocyanatophenyl)-2-(1-pyrrolidinyl)ethyl]acetamide (DIPPA), and methyl-naltrexone] given 15 min after the agonist. All agonists produced dose-related hypothermia, although at low doses, morphine and U50,488H produced hyperthermia. The effects of morphine and fentanyl were antagonized by naloxone and by the μ1antagonist naloxonazine. The δ2 antagonist naltriben potentiated the hypothermic effect of μ agonists. SNC80-induced hypothermia was blocked by the δ antagonist naltrindole but not by the δ1 antagonist BNTX. Depending on the dose, the δ2 antagonist naltriben produced either a potentiation or an attenuation of the effect of SNC80. U50,488H-induced hypothermia was antagonized by the κ antagonist nor-binaltorphimine but not by acute treatment with the irreversible κ antagonist DIPPA. The peripherally acting opioid loperamide produced hypothermia that could be blocked by several μ-, δ-, or κ-selective antagonists as well as the peripherally acting antagonist methyl-naltrexone. Methyl-naltrexone produced a weak potentiation of morphine-, fentanyl-, and U50,488H-induced hypothermia, whereas a significant attenuation of SNC80-induced hypothermia was observed. In conclusion, at high doses, morphine- and fentanyl-induced hypothermia may involve composite action on μ, κ, and possibly δ opioid receptors after initial activation. In the mediation of δ opioid-induced hypothermia, no clear selectivity between the δ1 and δ2subtypes was defined. The studies provide new evidence that maintenance of the initial effects of agonist/receptor activation vary with the agonist and the receptor. The existence of both central and peripheral components of opioid-induced hypothermia is also emphasized.
It has long been recognized that opioids such as morphine can produce a range of effects on body temperature in a number of species including man (Su et al., 1987; Adler et al., 1988; Wheelahan et al., 1998). The available data indicate that the species and strain, the ambient temperature, the level of restraint, the dose, and the specific opioid used may greatly affect thermoregulatory responses to opioids. In particular, the distinct roles of the μ, δ, and κ receptor types may be important in understanding the mechanisms of opioid-induced effects on body temperature, and these receptors may also play specific roles in thermoregulation (Spencer et al., 1988, 1990; Handler et al., 1992, 1994; Wilson and Howard, 1996).
Opioid receptor subtypes have been suggested on the basis of binding and pharmacological studies, although their relevance to the field of thermoregulation has not been fully evaluated. The existence of μ1 and μ2 receptor subtypes was proposed to explain the presence of a high- and a low-affinity μ receptor site using the μ1antagonist naloxonazine (Pasternak et al., 1980; Wolozin and Pasternak, 1981). The subdivision of the δ opioid receptor was proposed after several observations including differential antagonism of the effects of δ agonists by BNTX and naltriben (Sofuoglu et al., 1991, 1993), which are δ1 and δ2antagonists, respectively. Subdivision of the κ receptor is not well supported by in vivo evidence due to the lack of subtype-selective antagonists.
The effects on body temperature of morphine and other narcotic analgesics, which act primarily on the μ opioid receptor, are biphasic in rats and mice, with low doses producing hyperthermia and higher doses resulting in hypothermia at thermoneutral ambient temperatures (Rosow et al., 1980; Geller et al., 1983). In both of these species, however, higher and lower environmental temperature can profoundly affect body temperature responses to morphine and similar opioids (Rosow et al., 1980; Handler et al., 1994). At cool ambient temperatures, dose-related hypothermia was measured, whereas warm ambient temperatures resulted in dose-related hyperthermia. This has been demonstrated using partially restrained mice at ambient temperatures of 20, 25, or 30°C following subcutaneous injection of several narcotic analgesics from different chemical classes (Rosow et al., 1980). Comparable findings were obtained in rats at ambient temperatures of 5, 24, or 32°C following intraperitoneal or intracerebral morphine (Paolino and Bertrand, 1968). In addition, i.c.v. administration of the μ-selective agonist PL-017 in rats resulted in hypothermia at an ambient temperature of 5°C but hyperthermia at 30°C (Handler et al., 1994). These changes are due to alterations in oxygen consumption and heat loss (Adler et al., 1988). Morphine-induced hyperthermia and hypothermia in mice can be antagonized by naloxone, which provides further evidence for the involvement of opioid receptors (Rosow et al., 1982).
Changes in rodent body temperatures induced by δ opioid agonists have been investigated mainly through the use of peptide agonists. Administration of i.c.v. DPDPE to rats resulted in marked hypothermia followed by a rebound hyperthermic effect at high doses (Spencer et al., 1988). In a similar study, a hypothermic effect was produced at an ambient temperature of 5°C, whereas no effect was measured at 30°C (Handler et al., 1994). In addition, ambient temperatures of 4, 22, and 34°C were shown to affect responses to i.c.v. [d-Ala2]deltorphin II such that hypothermic potency was increased by lowering ambient temperature (Broccardo and Improta, 1992). These responses were also significantly reduced by naltrindole. The recently introduced nonpeptide δ agonist SNC80 has been shown to produce hypothermia in rats after intraperitoneal administration (Pohorecky et al., 1999).
Many authors have reported hypothermia in rodents after systemic or central administration of κ agonists, especially the selective nonpeptide agent U50,488H (Geller et al., 1983, 1986; Spencer et al., 1990; Handler et al., 1994). In addition, central administration of U50,488H in rats produced hypothermia at an environmental temperature of 20°C but no effect at 29°C (Mandenoff et al., 1991). Rebound hyperthermia following initial hypothermia has been reported after high i.c.v. doses of U50,488H in rats (Spencer et al., 1988). The hypothermic effect of a more potent κ agonist TRK-820, was shown to be blocked by the selective κ antagonist nor-binaltorphimine but not by naloxone or naltrindole (Endoh et al., 1999), indicating the presence of a specific κ-mediated mechanism.
Pretreatment with specific antagonists has been used as a method for providing evidence for the role of given receptors in mediating an effect. In contrast to this, administering antagonists after agonists can determine the importance of maintaining the initial receptor activation as well as uncover changes in the role of receptor systems during the progression of the event. Such information about the role of opioid receptors in body temperature could help in understanding the dynamics of opioid-induced hypothermia and prove useful in using body temperature as a means of characterizing opioids. Therefore, the ability of different opioid antagonists to alter hypothermia in opioid-pretreated mice, with respect to the μ, δ and κ receptors and their subtypes, was compared in the present study. To do so, antagonists were administered when hypothermia had started to develop, after a fixed duration following opioid agonist pretreatment. Thus, evidence was obtained about the importance of the agonist/receptor activity in maintaining the initial role of that receptor. Morphine and fentanyl were selected as classic narcotic analgesics with strong μ opioid activity, SNC80 as a selective δ agonist, and U50,488H as a selective κ agonist (Corbett et al., 1999). A range of antagonists with different receptor-selectivity profiles were used: naloxone (μ>δ/κ), β-funaltrexamine (irreversible μ), naloxonazine (μ1), naltrindole (δ), BNTX (δ1), naltriben (δ2), nor-binaltorphimine, (κ), and DIPPA (irreversible κ) (Corbett et al., 1999). To evaluate the peripherally mediated effect of opioids, we also selected the opioid agonist loperamide and the opioid antagonist methyl-naltrexone, since these agents penetrate poorly into the central nervous system (Van Nueten et al., 1979; Yuan and Foss, 1999). We selected a controlled laboratory ambient temperature of 22°C and used unrestrained animals to avoid stress-related effects that may influence thermoregulation (del Rio-Garcia et al., 1985; Adler et al., 1988) as well as alter endogenous opioid systems (Vaswani et al., 1988;Pohorecky et al., 1999).
Approval from the Institutional Animal Care and Use Committee was obtained prior to performing the described experiments. Male NMRI mice weighing 30 to 40 g were used. Mice were housed for 2 weeks in colonial stock cages following arrival from Iffa Credo (L'Arbresele, France). Animals were transferred to individual housing on the day prior to testing to allow overnight habituation. Food and water were available ad libitum at all times. The environmental temperature was controlled (22 ± 1°C), and the laboratory was maintained on a 12-h light/dark cycle (AM/PM). All experiments were carried out during the light phase.
Temperature Test Method
All temperatures were measured using a Comark C9001 thermometer (Comark, Sheffield, UK) and probe (length, 2.5 cm; diameter, 1 mm). Mice were unrestrained; they were individually removed from their housing for each temperature measurement and returned immediately afterward. Animals were held only by index finger and thumb at the base of the tail with all paws resting on the workbench. This allowed insertion of the probe without risk of tissue damage and without obvious distress. The probe was manually inserted 2.5 cm into the rectum and allowed to equilibrate for 5 s.
Experiment 1: Effects of Agonists.
Different doses of morphine, fentanyl, SNC80, U50,488H, or loperamide were selected from the metric series: 0.16, 0.63, 2.5, 10, and 40 mg/kg (saline control group, n = 20; opioid test groups, n = 10 per dose). Intraperitoneal injection of agonists immediately followed a preliminary temperature measurement. Rectal body temperatures were then measured every 30 min until 150 min after agonist treatment.
Experiment 2: Interactions between Agonists and Antagonists.
A single fixed dose of each agonist was selected from experiment 1, based on the presence of a strong hypothermic effect and reversal to baseline over time. The selected doses were 40 mg/kg morphine, 2.5 mg/kg fentanyl, 40 mg/kg SNC80, 40 mg/kg U50,488H, and 2.5 mg/kg loperamide. Fixed doses of the antagonists (0.63, 2.5, and 10 mg/kg) were tested against each agonist (saline control group,n = 40; agonist controls, n = 20 per dose; agonist versus antagonist, n = 10 per dose). To do so, 15 min prior to injection of the antagonist, preliminary body temperatures were measured, followed immediately by agonist pretreatment. Successive temperatures were then measured every 15 min until 45 min after antagonist treatment, which is 60 min after the agonist treatment. The effects on rectal temperature of the above selected doses of antagonists were assessed by taking a preliminary temperature measurement followed by injecting the test dose and then measuring every 15 min for 60 min (n = 10 per group).
Morphine-HCl was purchased from Belgopia SA (Louvain-La-Neuve, Belgium). Fentanyl-HCl and loperamide-HCl were obtained from Janssen Pharmaceutica (Beerse, Belgium). U50,488-HCl [trans-(dl)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]- benzeneacetamide], naloxone-HCl, naloxonazine-2HCl, β-funaltrexamine-HCl, naltrindole-HCl, naltriben mesylate, nor-binaltorphimine-2HCl, methyl-naltrexone-2HCl, SNC80, DIPPA, and BNTX were purchased from Tocris Cookson Ltd. (Bristol, UK). All drugs were freshly prepared as aqueous solutions prior to experimentation. Drugs were administered intraperitoneally in 10 ml/kg volumes per injection. All doses refer to base equivalents. Control animals received an equivalent volume of sterile physiological saline (0.9% NaCl; Baxter, McGaw Park, IL). All injections were given intraperitoneally.
All data values are expressed as mean ± S.E.M. Differences with regard to pre- and postinjection measurements were evaluated using a Wilcoxon signed rank test (two-tailed). Differences between experimental conditions were evaluated using a Mann-WhitneyU test (two-tailed) (Siegel, 1956). Asterisks indicate statistical significance: *P < 0.05; **P < 0.01; ***P < 0.001.
Based on the large number of statistical tests carried out between agonist/antagonist groups and agonist/vehicle groups, criteria were set for determination of the presence of interactions (Table1).
Summary of agonist/antagonist interactions
Experiment 1: Effects of Agonists (Fig.1).
Morphine, fentanyl, SNC80, U50,488H, and loperamide all produced changes in rectal body temperature compared with saline (Fig. 1). The mean preinjection body temperature of the saline control group (n = 20) was 37.32 ± 0.11°C. Subsequent measurements until 120 min after the saline injection were greater than the preliminary value, with the highest mean body temperature of 37.63 ± 0.12°C occurring 90 min after injection (★★, P = 0.0054).
Effects of intraperitoneal opioids on mouse rectal body temperature. Given are the mean ± S.E.M. changes in rectal body temperature over time for the various doses (milligrams per kilogram; see panels), n = 10 for opioid test groups, n = 20 for saline controls. Differences between opioid test groups and saline controls at the various time points were evaluated using a Mann-Whitney U test (two-tailed). The asterisks indicate statistical significance (★,P < 0.05; ★★, P < 0.01; ★★★, P < 0.001).
Morphine and U50,488H produced dual responses with low doses resulting in hyperthermia and higher doses resulting in hypothermia. Lasting hyperthermia, reaching a maximum of 0.86 ± 0.18°C was measured 150 min after 2.5 mg/kg morphine. Higher doses of morphine produced hypothermia, which returned to baseline, with a maximal effect of −2.21 ± 0.57°C measured 60 min after the 40 mg/kg dose. At a dose of 10 mg/kg, U50,488H produced a maximal hyperthermic effect of 0.97 ± 0.14°C measured 30 min after injection, before returning to baseline after 90 min. U50,488H produced a marked decrease in body temperature of −2.41 ± 0.42°C that occurred 30 min after the 40 mg/kg dose, returning to baseline between 60 and 90 min followed by a continued rise to a maximum of 1.02 ± 0.17°C after 120 min.
Fentanyl, SNC80, and loperamide all produced dose-dependent hypothermia. Fentanyl produced long-lasting hypothermia at the 2.5 mg/kg dose level, which reached a maximum of −2.39 ± 0.14°C at 30 min after injection. The hypothermic effect of 40 mg/kg SNC80 was also long lasting, with a maximal decrease of −4.13 ± 0.20°C at 30 min after injection. Loperamide at 2.5 mg/kg produced a drop in body temperature of −3.06 ± 0.36°C at 30 min after injection, which returned to baseline after 90 min.
Morphine (from 2.5 mg/kg) and fentanyl (from 0.16 mg/kg) also produced μ opioid behavioral changes including arched back, Straub-tail, and motoric excitation. These effects were not observed with loperamide at the doses tested, which instead produced an observed decrease in the activity of the animals from 2.5 mg/kg upward. SNC80 and U50,488H produced an observed decrease in the activity of the animals only at the 40 mg/kg dose level.
Experiment 2: Interactions between Agonists and Antagonists (Figs.2-7; Table 1).
In the saline/saline group (n = 40), the preinjection rectal temperature was 37.39 ± 0.10°C, rising to 37.88 ± 0.14°C after 15 min following the first saline injection (** P = 0.0012). Rectal temperatures were found to increase steadily over time, reaching a maximum of 38.20 ± 0.10°C measured 45 min after the second injection.
Pretreatment of the different agonists (n = 20) 15 min prior to a saline injection produced hypothermic effects lasting over the duration of the experiment that were comparable to those measured in experiment 1. All agonists produced their maximal decreases in body temperature at 30 min after treatment: 40 mg/kg morphine (−3.66 ± 0.25°C), 2.5 mg/kg fentanyl (−2.26 ± 0.36°C), 40 mg/kg SNC80 (−4.98 ± 0.20°C), 40 mg/kg U50,488H (−3.08 ± 0.37°C), and 2.5 mg/kg loperamide (−2.98 ± 0.25°C) (Figs.3-7). The 15-min duration between the agonist pretreatment and the saline or antagonist injection allowed comparisons to be made between the effects of the pretreatment in the agonist/saline group against those in the agonist/antagonist groups. In only a single experiment was a significant difference found: U50,488H/saline (−1.62 ± 0.17°C) was significantly different than the U50,488H/naltriben 2.5 mg/kg group (−0.71 ± 0.30°C; P = 0.0145) (Fig.6).
Effects of different opioid antagonists on U50,488H-induced hypothermia. Given are the mean ± S.E.M. changes in rectal body temperature. Fifteen minutes prior to injection of the antagonist, preliminary body temperatures were measured, animals were pretreated with U50,488H (40 mg/kg i.p.), and a baseline control group received saline (●), n = 40. At 0 min, the U50,488H-pretreated animals received an antagonist [0.63 (▾), 2.5 (▿), or 10 (▪) mg/kg i.p, n = 10 for each group], whereas the U50,488H control group (○),n = 20 and the baseline control group received saline. Differences between U50,488H/antagonist groups and the U50,488H control group at the various time points were evaluated using a Mann-Whitney U test (two-tailed). The asterisks indicate statistical significance (★, P < 0.05; ★★,P < 0.01; ★★★, P < 0.001).
Of the antagonists tested for intrinsic effects on body temperature, β-funaltrexamine and naltriben produced small decreases in body temperature at the highest dose tested (10 mg/kg) (Fig.2). Maximal effects of −0.18 ± 0.23 and −0.26 ± 0.17°C, respectively, were measured 60 min after injection. BNTX at a dose of 10 mg/kg produced a hyperthermia of 1.38 ± 0.16°C measured 60 min after injection (Fig. 2). DIPPA also produced hyperthermia with a maximal effect of 1.38 ± 0.18°C measured 15 min after injection of a 2.5 mg/kg dose (Fig. 2). Naloxone, naloxonazine, naltrindole, nor-binaltorphimine, and methyl-naltrexone produced no effects on body temperature at the doses tested.
Effects of intraperitoneal opioid antagonists on mouse rectal body temperature. Given are the mean ± S.E.M. changes in rectal body temperature over time for the various doses (milligrams per kilogram; see panels), n = 10 for opioid antagonist test groups, n = 40 for saline controls. Differences between opioid antagonist test groups and saline controls at the various time points were evaluated using a Mann-WhitneyU test (two-tailed). The asterisks indicate statistical significance (★, P < 0.05; ★★,P < 0.01; ★★★, P < 0.001).
Morphine-induced hypothermia was antagonized strongly by doses of 0.63, 2.5, and 10 mg/kg of both naloxone and naloxonazine and weakly by 0.63 and 2.5 mg/kg DIPPA (Fig. 3). The strongest antagonism was observed with 2.5 mg/kg naloxone, which reduced the effect of morphine after 45 min to −0.45 ± 0.22°C compared with −3.22 ± 0.24°C for the morphine control group. A weak potentiation of morphine-induced hypothermia was measured 30 and 45 min after 10 mg/kg DIPPA, reaching a maximum at 45 min (−5.19 ± 0.66°C) (Fig. 3). Weak potentiation of morphine-induced hypothermia was measured 30 min after 0.63 mg/kg naltrindole (−4.14 ± 0.25°C) and 2.5 mg/kg methyl-naltrexone (−4.23 ± 0.27) compared with −3.38 ± 0.24°C for the morphine control group (Fig. 3).
Effects of different opioid antagonists on morphine-induced hypothermia. Given are the mean ± S.E.M. changes in rectal body temperature. Fifteen minutes prior to injection of the antagonist, preliminary body temperatures were measured, animals were pretreated with morphine (40 mg/kg i.p.), and a baseline control group received saline (●), n = 40. At 0 min, the morphine-pretreated animals received an antagonist [0.63 (▾), 2.5 (▿), or 10 (▪) mg/kg i.p, n = 10 for each group], whereas the morphine control group (○),n = 20 and the baseline control group received saline. Differences between morphine/antagonist groups and the morphine control group at the various time points were evaluated using a Mann-Whitney U test (two-tailed). The asterisks indicate statistical significance (★, P < 0.05; ★★,P < 0.01; ★★★, P < 0.001).
Fentanyl-induced hypothermia was antagonized by 10 mg/kg naloxone as evidenced by significantly higher temperatures occurring 15, 30, and 45 min after naloxone compared with the fentanyl control group (Fig.4). The effect of fentanyl was reduced to 0.35 ± 0.33°C measured 30 min after 10 mg/kg naloxone compared with −1.89 ± 0.39°C for the fentanyl control group. In addition, a weak antagonism was observed 15 min after 10 mg/kg naloxonazine, reducing the fentanyl hypothermia to −0.98 ± 0.24°C compared with −2.26 ± 0.36°C for the fentanyl control group (Fig. 4). Potentiation of fentanyl-induced hypothermia was observed 30 and 45 min after 10 mg/kg naltriben in a manner similar to that seen with morphine-induced hypothermia (Figs. 3 and 4). This effect reached −3.57 ± 0.60°C measured 30 min after 10 mg/kg naltriben. Fentanyl-induced hypothermia was also weakly potentiated 30 and 45 min after 0.63 mg/kg methyl-naltrexone with a reduction in body temperature to −3.30 ± 0.38°C after 30 min (Fig. 4).
Effects of different opioid antagonists on fentanyl-induced hypothermia. Given are the mean ± S.E.M. changes in rectal body temperature. Fifteen minutes prior to injection of the antagonist, preliminary body temperatures were measured, animals were pretreated with fentanyl (2.5 mg/kg i.p.), and a baseline control group received saline (●), n = 40. At 0 min, the fentanyl-pretreated animals received an antagonist [0.63 (▾), 2.5 (▿), or 10 (▪) mg/kg i.p, n = 10 for each group], whereas the fentanyl control group (○),n = 20 and the baseline control group received saline. Differences between fentanyl/antagonist groups and the fentanyl control group at the various time points were evaluated using a Mann-Whitney U test (two-tailed). The asterisks indicate statistical significance (★, P < 0.05; ★★,P < 0.01; ★★★, P < 0.001).
SNC80-induced hypothermia was dose-dependently antagonized by naltrindole. Significant antagonism was also observed with methyl-naltrexone. In addition, antagonism was measured after naloxone and β-funaltrexamine. Following 10 mg/kg naltrindole, the effect of SNC80 was reduced at all of the time points measured, with the greatest differences from the SNC80 control group occurring after 15 and 30 min (Fig. 5). These values were 1.61 ± 0.39 and −1.10 ± 0.38°C, respectively, compared with −4.98 ± 0.2 and −4.42 ± 0.32°C for the SNC80 control group. Methyl-naltrexone reduced the effect of SNC80 measured 30 and 45 min after doses of 0.63, 2.5, and 10 mg/kg (Fig. 5). The greatest effect of methyl-naltrexone was measured 45 min after the 10 mg/kg dose, which reduced the decrease in rectal temperature to −1.62 ± 0.32°C compared with the SNC80 control group value of −3.41 ± 0.36°C. After 15 min following 10 mg/kg naloxone, SNC80-induced hypothermia was reduced to −3.82 ± 0.32°C (Fig. 5). A similar reduction to −3.56 ± 0.27°C was measured 15 min after 0.63 mg/kg β-funaltrexamine (Fig. 5). Mixed effects on SNC80-induced hypothermia occurred in response to naltriben, with antagonism occurring 15 and 30 min following 2.5 mg/kg naltriben and a potentiation occurring 45 min after the 10 mg/kg dose (Fig. 5).
Effects of different opioid antagonists on SNC80-induced hypothermia. Given are the mean ± S.E.M. changes in rectal body temperature. Fifteen minutes prior to injection of the antagonist, preliminary body temperatures were measured, animals were pretreated with SNC80 (40 mg/kg i.p.), and a baseline control group received saline (●), n = 40. At 0 min, the SNC80-pretreated animals received an antagonist [0.63 (▾), 2.5 (▿), or 10 (▪) mg/kg i.p, n = 10 for each group], whereas the SNC80 control group (○), n = 20 and the baseline control group received saline. Differences between SNC80/antagonist groups and the SNC80 control group at the various time points were evaluated using a Mann-Whitney U test (two-tailed). The asterisks indicate statistical significance (★,P < 0.05; ★★, P < 0.01; ★★★, P < 0.001).
Only nor-binaltorphimine produced a clear antagonism of U50,488H-induced hypothermia (Fig. 6). The greatest reduction was observed with 10 mg/kg nor-binaltorphimine, causing reductions to −0.14 ± 0.22 and 0.23 ± 0.22°C after 30 and 45 min, respectively, compared with −2.12 ± 0.26 and −1.32 ± 0.24°C for the U50,488H control group. Rectal temperatures 15, 30, and 45 min following 2.5 mg/kg naltriben were also significantly higher than the U50,488H control group, although as mentioned above, pretreatment of U50,488H in this test group produced a smaller hypothermia than the control group (Fig. 6). Potentiation of U50,488H-induced hypothermia was observed 45 min following 0.63 (to −2.44 ± 0.37°C) and 10 mg/kg (to −4.17 ± 0.88°C) DIPPA (Fig. 6). Methyl-naltrexone at a dose of 10 mg/kg produced weak potentiation (to −2.75 ± 0.36°C) of the hypothermic effect of U50,488H after 45 min (Fig. 6).
After 45 min, naloxone (10 mg/kg), naltrindole (10 mg/kg), BNTX (2.5 mg/kg), and nor-binaltorphimine (2.5 mg/kg) reduced the hypothermic effect of loperamide (−1.73 ± 0.24°C) to above 0°C, representing a marked antagonism (Fig.7). Similarly, β-funaltrexamine (10 mg/kg), naloxonazine (2.5 and 10 mg/kg) and methyl-naltrexone (0.63, 2.5 and 10 mg/kg) reduced loperamide-induced hypothermia to within −0.35°C after 45 min (Fig. 7). The effect of naltriben was somewhat weaker with the greatest antagonism to −0.72 ± 0.40°C measured 45 min after a 10 mg/kg dose (Fig. 7). Of the nine antagonists tested, only DIPPA produced no effect on loperamide-induced hypothermia (Fig.7).
Effects of different opioid antagonists on loperamide-induced hypothermia. Given are the mean ± S.E.M. changes in rectal body temperature. Fifteen minutes prior to injection of the antagonist, preliminary body temperatures were measured, animals were pretreated with loperamide (2.5 mg/kg i.p.), and a baseline control group received saline (●), n = 40. At 0 min, the loperamide-pretreated animals received an antagonist [0.63 (▾), 2.5 (▿), or 10 (▪) mg/kg i.p, n = 10 for each group], whereas the loperamide control group (○),n = 20 and the baseline control group received saline. Differences between loperamide/antagonist groups and the loperamide control group at the various time points were evaluated using a Mann-Whitney U test (two-tailed). The asterisks indicate statistical significance (★, P < 0.05; ★★, P < 0.01; ★★★, P< 0.001).
Decreases in rectal body temperature in mice were brought about by systemic administration of several different opioid agonists that act on μ, δ or κ opioid receptors. Morphine and U50,488H were also shown here to produce hyperthermia at low doses. The effects shown here with morphine, fentanyl, SNC80, and U50,488H are comparable to those reported in the current literature (see Introduction).
However, certain observations with single compounds warrant further discussion. First, hyperthermia can be expected from μ agonists although no hyperthermia was observed with fentanyl, which is far more selective for μ receptors than morphine (Maguire et al., 1992). At a dose of 0.16 mg/kg fentanyl, no effects on body temperature were seen, although this dose readily produces marked and lasting antinociception in mice (Niemegeers et al., 1976). It is possible that 0.16 mg/kg fentanyl represents the balance point of a dual dose-response curve mediated by different opioid receptor types, as previously demonstrated for morphine (Chen et al., 1996). In addition, the dose of fentanyl required to produce hypothermia was relatively high at 0.63 mg/kg, indicating that δ and κ receptors could have been activated.
With regard to the role of the κ receptor, hyperthermia resulted 30 min after 10 mg/kg U50,488H, and at 40 mg/kg, hypothermia followed by rebound hyperthermia was seen. Similarly, rebound hyperthermia was measured following an initial hypothermia after i.c.v. administration of U50,488H in unrestrained rats (Spencer et al., 1988). Hyperthermia directly following administration of a κ agonist has not been reported previously. However, since temperatures were determined every 30 min in the characterization of the dose-response curve, the possibility that an initial short-lasting hypothermia was missed cannot be ruled out.
In addition to the findings with centrally penetrating agents, we have also found that loperamide produced a dose-dependent decrease in rectal body temperature in mice. Since loperamide does not cross the blood-brain barrier (Van Nueten et al., 1979), this finding indicates that opioid receptors in the periphery can be stimulated to produce hypothermia in mice. The opioid antagonist methyl-naltrexone does not cross the blood-brain barrier and exhibits a relative order of selectivity: μ > κ > δ (Yuan and Foss, 1999). Our findings that methyl-naltrexone strongly antagonized the decreased body temperature produced by loperamide but not morphine or fentanyl, further confirms the existence of a peripheral mechanism of opioid-induced hypothermia. Whereas loperamide is an opioid agonist only in the periphery, centrally penetrating agents bind to opioid receptors at both the peripheral and central levels, thus activating both mechanisms. Furthermore, it is possible that the hypothermic effects of peripheral opioid receptor activation may not simply be additive to the effects of central activation if both occur together, as evidenced by the weak potentiation of morphine-, fentanyl-, and U50,488H-induced hypothermia caused by methyl-naltrexone. For the opioids mentioned, central mechanisms may predominate. By contrast, hypothermia induced by the δ agonist SNC80, was significantly reduced by methyl-naltrexone, indicating a significant peripherally mediated mechanism of action for systemic δ opioids.
In the preoptic anterior hypothalamus, there is convincing evidence that μ receptors mediate hyperthermia, whereas κ receptors mediate hypothermia in unrestrained rats (Xin et al., 1997). In addition, antisense oligonucleotides against μ opioid receptors but not κ receptors significantly attenuated the hyperthermia induced by low doses of systemic morphine, whereas the reverse was true for the hypothermia induced by high doses (Chen et al., 1996). Such results provide clear evidence for the roles of central μ and κ opioid receptors in unrestrained rats and further demonstrate that the dominant site of action of morphine-induced hypothermia is within the brain, not the periphery. Our findings relating to μ and κ receptor tonic balance must therefore be closely addressed. In particular, no effect on morphine- or fentanyl-induced hypothermia was evident with the specific κ antagonist nor-binaltorphimine, which clearly contrasted with previous work where animals were pretreated with antagonists (Chen et al., 1996; Xin et al., 1997). Second, the reversal of morphine- and fentanyl-induced hypothermia observed after naloxone is unlikely to be due solely to κ antagonism, as the more μ-selective agent naloxonazine produced similar effects. The finding that morphine and fentanyl produced hypothermia only at relatively high and perhaps nonselective doses may be important. However, in the presence of an established hypothermia induced by these agents, κ antagonism has been found to be insufficient to reduce hypothermia. If a μ-hyperthermia/κ-hypothermia model is accepted, then these results are the first to show that the modulatory roles of the μ and κ opioid receptors change as a result of continued activation. These changes may be part of a dynamic balance of opioid receptor occupation and the effect on receptor function of body temperature itself. Failure of κ antagonism but the success of μ antagonism to reverse morphine- and fentanyl-induced hypothermia could also be considered consequences of sudden receptor blockade producing rebound effects and upsetting this balance. Systemic blockade of μ receptors after even a short duration of morphine exposure is known to trigger a withdrawal-like stress response (Houshyar et al., 2001), which could potentially alter the opioid control of body temperature. Naloxonazine has been proposed to bind selectively to a high-affinity μ1 site, and this could indicate that the role of the μ receptor is limited to the μ1receptor type. The role of the μ receptor may be specific to this agent, since although naloxone produced similar results, this antagonist is relatively unselective and so may have produced its effects via a different mechanism. The administration of antagonists during the development of hypothermia rather than as a pretreatment, as well as the specific antagonists used, most likely account for the effects of the μ receptor in the present work.
The possible modulatory role of peripheral opioid receptors has not previously been investigated. Giving antisense oligonucleotide against the κ receptor showed a large but not fully complete blockade of hypothermia after 30 mg/kg subcutaneous morphine (Chen et al., 1996). Residual κ receptor activity was suggested, but this could equally be due to the continued peripheral activity of morphine. The peripheral occupation of opioid receptors may be trivial during concomitant central occupation, but as loperamide demonstrates, the activation of peripheral opioid receptors on their own is highly significant. Little is know about the peripheral mechanism of opioid-induced hypothermia and the consequences of sudden blockade. The importance of this could be tested by giving i.c.v. naloxonazine after high doses of i.c.v. and systemic morphine.
Further considerations relate to the use of different species and strains with regard to thermoregulation at the specific laboratory temperature or stress-related differences. Evidence that highly selective μ agonists can produce hypothermia in certain settings is a further consideration. First, PL-017 produced hypothermia in rats exposed to an environmental temperature of 5°C (Handler et al., 1994). Before the μ specificity of this hypothermia was shown, it had been demonstrated previously that morphine lowers body temperature by suppression of central thermogenic responses to the low environmental temperature (Lotti et al., 1966). There may exist differences in the extent to which different strains respond to environmental temperatures. Second, DAMGO was shown to produce dose-dependent hypothermia in restrained rats (Spencer et al., 1988). The effect of restraint as a physiological stressor, which may induce release of endogenous opioids, was used as an explanation for this finding. Restraint diminishes morphine-induced hyperthermia and enhances high-dose hypothermia (Adler et al., 1988). This shift may also be indicative of a change in the role of the μ receptor during stress.
There are several principle mechanisms by which drugs can alter body temperature. The preoptic anterior hypothalamus serves as the controlling thermoregulatory set point (Adler et al., 1988). Changes in set point, as opposed to loss of heat control systems, can be demonstrated using different environmental temperatures through which animals are free to move (Cox et al., 1976). It has further been demonstrated that a rise in thermoregulatory set point causes vasoconstriction, which reduces heat loss (Adler et al., 1988). After observations from several species, morphine-induced hypothermia has been primarily attributed to a decrease in oxygen consumption rather than increased heat loss (Lotti et al., 1966; Lin et al., 1980). These observations indicate that there are several central and peripheral sites at which drugs, and possibly opioids, can alter the control of body temperature.
A decrease in activity of animals treated with loperamide was observed in the present work. Similar results have been obtained from place preference and locomotor studies (Bechara and van der Kooy, 1985;Bedingfield et al., 1999). However, it has been suggested that the body temperature effects of opioids do not correlate well with motoric activity (Adler et al., 1988), and this effect alone cannot account for the dramatic hypothermia seen in mice following loperamide. In addition, we have observed increased motoric activity in mice after morphine and fentanyl at doses that induced hypothermia. Loperamide does not directly affect central control of body temperature in the same way as centrally penetrating agents, and therefore the observed hypothermia is more likely to be due to increased heat loss rather than decreased oxygen consumption and/or decreased metabolic heat production. Further experiments to determine oxygen consumption and warm/cold place preference after loperamide would provide valuable insight into the mechanism of action of this agent.
The results presented here in mice show that several different opioid antagonists from different chemical classes and exhibiting different selectivity profiles antagonize the hypothermic effects of loperamide. If this agent produced its effects by increasing heat loss, the results may suggest that this mechanism is more readily reversible than the induced decrease in heat production produced by centrally penetrating opioids.
The irreversible μ antagonist β-funaltrexamine did not significantly alter either morphine or fentanyl-induced hypothermia. However, the receptor binding properties of β-funaltrexamine are noncompetitive (Corbett et al., 1985), and due to the study design, which focused on acute interactions, full antagonist activity may not have developed. The pharmacological profile of this agent is somewhat different to the other μ antagonists, however, since it possesses an initial κ agonist activity and has been shown to produce analgesia in mice (Ward et al., 1982; Qi et al., 1990). In addition, we have shown here that a 10 mg/kg dose of β-funaltrexamine can induce hypothermia in mice, which is probably due to κ receptor stimulation.
The δ1 antagonist BNTX produced weak antagonism of morphine-induced hypothermia. However, this agent produced a small but significant increase in body temperature when given alone. The δ2 antagonist naltriben at the 10 mg/kg dose level produced a marked potentiation of both morphine- and fentanyl-induced hypothermia. However, 10 mg/kg naltriben was found to produce a small decrease in body temperature by its self. In addition, the nonsubtype-selective δ antagonist naltrindole produced a weak potentiation of the effects of morphine. It has been suggested that μ and δ receptors may be complexed, and pharmacological studies have provided evidence for specific interactions. For example, modulation of morphine antinociception by δ agonists was found to be sensitive to β-funaltrexamine but not μ1 naloxonazine, providing evidence for the functional role of complexed and noncomplexed μ and δ receptors (Heyman et al., 1989). In addition, locomotor stimulation and place preference effects of morphine are reduced by naltriben (Narita et al., 1993; Kamei et al., 1997).
SNC80-induced hypothermia was markedly antagonized by the δ opioid antagonist naltrindole and also by the peripheral antagonist methyl-naltrexone. However, the degree of antagonism with methyl-naltrexone was less than with naltrindole. The failure of the δ subtype-selective agents to produce a strong antagonism of the effects of SNC80 may indicate a lack of δ1/δ2 subtype specificity with regard to δ opioid-induced hypothermia. However, the δ2-selective antagonist naltriben at the 2.5 mg/kg dose level significantly reduced SNC80-induced hypothermia. In contrast, 10 mg/kg naltriben, a dose that produces hypothermia by itself, produced a significant increase in SNC80-induced hypothermia. It was also at this dose that naltriben potentiated the effects of morphine and fentanyl. It may be possible therefore that naltriben exhibits biphasic dose-response characteristics. We have also shown that naloxone and β-funaltrexamine significantly reduced the effect of SNC80, whereas naloxonazine produced no effect. Together, these observations provide further support for the existence of a functional pharmacological role for a μ/δ complex.
The κ opioid antagonist nor-binaltorphimine produced inhibition of U50,488H-induced hypothermia. In contrast, the irreversible κ antagonist DIPPA produced an increase in U50,488H-induced hypothermia from 2.5 mg/kg. It remains to be determined whether pretreatment with DIPPA would abolish hypothermia induced by a subsequent injection of U50,488H.
In summary, we have used a body temperature assay in mice to show that opioid-induced hypothermia can be modulated by multiple opioid receptor systems, which have the ability to interact with each other. At the relatively high doses used, morphine- and fentanyl-induced hypothermia may involve composite action on μ, κ, and possibly δ opioid receptors. The consequences of sudden blockade of opioid receptors after their initial activation may be significant in understanding the reversibility of morphine- and fentanyl-induced hypothermia. We have also clearly emphasized the existence of both central and peripheral components of opioid-induced hypothermia in mice. In the mediation of δ opioid-induced hypothermia, no clear selectivity between the δ1/δ2 subtypes was defined. In addition, further evidence has been provided for the existence of specific μ/δ interactions at the in vivo pharmacological level.
We acknowledge Nancy Aerts for excellent technical assistance.
DOI: 10.1124/jpet.102.037655
BNTX
7-benzylidenenaltrexone
DIPPA
2-(3,4-dichlorophenyl)-N-methyl-N-[(1S)-1-(3-isothiocyanatophenyl)-2-(1-pyrrolidinyl) ethyl]acetamide
DAMGO
[d-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin
SNC80
(+)-4-[(αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoybenzyl]-N,N-diethylbenzamide
Accepted May 3, 2002.
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Journal of Pharmacology and Experimental Therapeutics September 1, 2002, 302 (3) 1253-1264; DOI: https://doi.org/10.1124/jpet.102.037655
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In the last few months, my work has taken a surprising turn. I'm having meetings about things that I don't think most history museum directors ever dream about. People are approaching us with some pretty incredible ideas–ideas that have made my jaw drop and my mind whirl. After about the third time, I started thinking about what caused all of this. And though I could be wrong, the motivations seem to boil down to three main things: our location, our reputation, and the fact that I spend an awful lot of time out in the community talking to people.
Some board members nodded. Some avoided looking me in the eye. Some gave me the side eye.
And last weekend, we celebrated another big project and big win for the neighborhood–the grand opening of the Lorenzo Hotel. This building, super visible from DHV, has been empty for years. It was an eyesore, overrun by homeless. Initially, the redevelopment proposal was for affordable housing, and the neighborhood fought that. Today, we have a gorgeous, funky boutique hotel with a pretty fabulous bar.
There was no question about whether or not I would go to the party–I wanted to celebrate that one of the big ideas for the Cedars was complete. And when it was mentioned that a few folks were renting hotel rooms that night, I decided to splurge and get one too.
It was a party unlike anything I've ever been too. Of course, there was lots of food and drink. But there were also aerialists spinning by the pool, mermaids swimming in the pool, body paint artists and fairies roaming around.
And most shocking, there was a line around the block of people trying to get in. At that party, a lot of people learned that there is life south of I-30.
Me, with neighborhood artist Jim and friend Stephanie. We didn't have to wait in a line to get in!
We've got a long way to go, both as a neighborhood and as an organization. Balancing the budget continues to be a real challenge. Quality of life issues are enormous. But I can't help but think big and continue to be incredibly optimistic. In a few weeks, we'll present to the Master Plan Committee and staff some initial ideas for DHV's future, and we'll be doing it at the Lorenzo Hotel. It just feels exactly right to think about the future in a place that is a few steps ahead of us.
The view from my hotel room. That green stuff just to the left of the big white building is DHV. And you can barely see the Dallas flag!
P. S. I wish I could be less vague about some of these big ideas and partnerships. I want to shout it from the rooftops! (and if I see you in person, I'll probably share). But nothing is official yet. Trust me–I'll share when I can.
You would think after two+ years, the questions would have stopped.
There are a lot of very good answers to these questions, some of which I've addressed in previous blog posts. I've gotten on my soap box more than once about the need for museums to be more involved in their communities–and to start thinking differently about what community involvement means. It's not just about getting people to walk through your doors.
But here's a new answer: I don't think I would have survived this past week without the past two years of increasing community involvement. And my museum would be in a very different place.
On Monday, we needed to make a call about whether or not to pursue a rain plan for our largest fundraiser, History with a Twist. During a two hour meeting, the forecast for rain on Saturday went from 40% to 80%. We decided to wait until Tuesday morning to make the call.
Usually, DHV can't do much about rain. We can cram about 200 people into the Pavilion, but with 300+ expected guests, food, silent auction, and drinks, there weren't any good options to keep it at DHV. However, when the 10 day forecast came out, with an 80% chance of rain, I emailed Karen, the ED at Vogel Alcove. I asked: "Is there any way we can move Twist to your building? I know you may have a lot of issues to consider regarding this request, but please think about." I was expecting a long conversation because this was a very, very big favor. Within a few hours, Karen wrote back "Of course. Whatever you need." I shouted Hallelujah at my desk. More than once.
First thing Tuesday, I had a long chat with my event chair, Don. Forecast varied depended on where you looked, but all said we would have severe weather on Friday night. This meant set up, particularly for sound and lighting, became more complicated. We knew Vogel would be a very tight fit, but I thought it would be better to spend the week stressing about things we could control, rather than things we can't. I decided to ask Helen, my director of sales, how she would advise a bride and get back to Don. While I was on the phone with Helen, my phone rang. The last time I ignored a call from the Ticket Office, a reporter had shown up. So I picked up–another reporter had arrived. I texted Don as I walked over, letting him know it would be a little while before I got back to him.
When I got back to the office, I called Don and we made the decision to proceed with moving Twist to Vogel. Helen and I had a quick meeting, and we got to work on contacting vendors and figuring out the setup.
In the midst of all this, I had a long conversation with Michael, one of my favorite neighborhood advocates–and a member of our board. The day before, there had been a rather contentious Public Safety Committee meeting at City Hall. CM Greyson asked a lot of questions regarding police plans regarding Tent Village, and they continued to state that it wasn't a priority. But this was the first time someone besides our council member, Adam Medrano, had asked any questions. This seemed like a small glimmer of light in what has been a very long, dark tunnel.
Earlier that morning, I had received an email from Stephanie, who is our primary contact for schools. As a result of Friday's Channel 8 story, schools were calling, concerned about their students' safety if they came to DHV. Two schools requested to talk to me directly. A few schools cancelled. Late Tuesday afternoon, I sent an email to Mayor Rawlings and Adam letting them know that I had just reassured two schools that their students would be safe on their field trips.
That evening was the monthly CBD (Central Business District) crime watch meeting. I hadn't planned on attending–I have been to a lot of crime watch meetings over the past year, and I can only tolerate them so often. Also, it was FYA book club night. But after hearing more about the Public Safety meeting and seeing a note that one of the agenda items was Tent Village, I figured I should probably go.
As I walked up, I happened to run into Adam. He told me that the letter writing campaign we launched on April 15 was working–and we needed to keep it up. He also mentioned the letter I had just written to the Mayor–and that he had already gotten a call from the Mayor's office. Another glimmer of light in the tunnel.
The Dallas Police Chief was there, which I hadn't realized when I made my decision to go. When the floor was opened for general questions, the very first question, not asked by me, was about their plans regarding Tent Village.
I want to pause for a moment to say this: at every single meeting I've attended regarding the current Dallas homeless crisis, I have never been the one to bring up Tent Village. Someone else always does it first. This isn't by design–there's no planning or coordination. It just happens. Do you know how gratifying that is? How good it feels to see all your advocacy work out in the community like that? I don't think there's a better expression of how the Cedars neighborhood feels about Dallas Heritage Village than what is said in these meetings.
That may be the moment when all the momentum we've been building as a community–the letter writing, the tweets, the meetings, the news stories–finally began to turn the tide. Chief Brown promised to make closing Tent Village a priority. He asked us to help with creating barriers to make it a less enticing spot. I responded that we had neighbors that have been talking about a cactus/rock garden for months. Enthusiastic nods around the room. At 7:15, I left to head to book club. I really needed a beer.
After a long trying process, most of tent Village is gone. This is been the culmination of the efforts of many many people. We hope we can remain that way. Some cleanup still has to get done Landscaping xcetera to prevent them from coming back. Many thanks to Chief David Brown Adam Medrano and all the people in The Cedars, DHV, and Farmers Market who made this happen over the past few months.thanks to all DPD and support from friends downtown.
Trey headed out as I called Michael. Several neighbors were in our small parking lot off Ervay, so I ran over there. We all kinda looked at each other in amazement, stunned that the city had finally taken action. We all know it was just a first step, that there is still much work to do–both to help the homeless and discourage the camp from forming again. However, we still decided that we needed a beer.
On Thursday, the forecast changed again. Late that afternoon a committee member asked the question I had been avoiding: can Twist be moved back to DHV? We started reaching out to key vendors to find out if they could change their set up schedule. They could. On Friday morning, I made the call–back to DHV! And I thanked Karen again, who responded "You know if you hadn't made all those plans, the forecast wouldn't have changed." Nothing about the time her staff spent answering our questions, planning the setup, all the week before their own big fundraiser. As I said in my remarks on Saturday, they are the definition of neighborly.
That evening, I went to the monthly Cedars Neighborhood Association meeting. We are the default hosts, but on Monday, with my cloudy crystal ball, I asked them to find a different location as I didn't want to ask anyone to stay late to host–and I knew I didn't want to. But with all that had happened, I knew I had to go. While I was eating dinner, the official word was spread that Tent Village would be closed in conjunction with Tent City on May 4. I spoke briefly about the landscape/barrier plans, and then I said "There are certainly challenges in running a museum in our neighborhood, but there's not another neighborhood in Dallas I would rather be in." And then I totally started crying and quickly sat down.
My Saturday started pretty early by my standards–breakfast at 8 with the Mayor Mike Rawlings and selected neighbors. it was on the calendar before the events of the past week, but the timing certainly felt fortuitous. We talked more about Tent Village, the challenges of being in the Cedars and feeling neglected by the Powers That Be. It was a very good conversation, though I remain somewhat pessimistic about any radical changes. And then, I headed to DHV to start setting up for Twist.
Saturday ended up being just about a perfect day, weather-wise. Not too humid, not too hot. It was a beautiful night at DHV. Many, many neighbors were there too–along with Adam Medrano, board members that have definitely had my back through all of this, my parents, family friends, and museum friends. It was a good night–we raised some money, had some fun, and I didn't tear up once.
DHV Leadership team: Me, Immediate Past Chair Kelly, Event Chair Don (driving), honorary chairs Ben & Marilyn (Sgt. Pepper!) and current chair Trey.
Could you ask a favor of one of your neighbors on the level of what I asked Karen?
If you were in the middle of a local political crisis, would your neighbors speak up for you?
Would you be invited to a "neighborhood" breakfast with the mayor?
Lots of work still to do, and the Dallas homeless crisis continues. Tent City and Tent Village will be closed on Wednesday. It will likely be another crazy week, but perhaps a bit calmer since Twist is now behind us. And no matter how crazy it gets, I know I have some neighbors and friends that are willing to have a drink with me as we attempt to build a better community.
No, you can't bring your frisbee.
No, we don't have a swimming pool available for your birthday party.
Yes, you do have to pay admission even though you're a Dallas taxpayer.
The "museum" is all around you, as soon as you walk through our gates.
In 2006, we changed our name to Dallas Heritage Village at Old City Park. Of course, name changes are never easy, and we still get asked all the time why we changed our name. My short (somewhat snarky) answer has always been: "Why would anyone want to go to an old city park?" And then people generally get it. Changing our name has solved many, many problems. We don't get the above questions any more. But, of course, there are other challenges.
Changing vocabulary is hard. There are still lots and lots of people out there that still use our old name or just say "the park." I never correct many of our long time supporters (after all, some of them have supported this organization longer than I've been alive. They can call us whatever they want), but if you got to know us post-2006, you better be not be calling us a park. As we began working with our new developer friends, I had to have a conversation about how they referred to us, emphasizing "history museum in park-like setting." Over the years, I've learned the hard way that people that primarily think of us as a park aren't going to respect our mission of preservation and education. For years, I've been working to eradicate the word park from our DHV vocabulary. But now I'm starting to have some second thoughts.
Danielle, wife of our programming partner, Matt Tolentino. Photo courtesy John Lehman, DHV volunteer photographer.
Yesterday was the 3rd Annual Dallas Jazz Age Sunday Social. This 1920s themed lawn party uses our grounds to their full potential. It's certainly a day when we're more park than museum. Thirteen hundred people showed up yesterday, the largest non-Candlelight event attendance we've had in 5 years. Though most people explored the museum, the prime attraction was sitting on our lawn, enjoying the first real spring day in Dallas. We closed at 5. At 6, we had to kick people off their picnic blankets. It was glorious. Matt, our partner for the event, uses the word park all the time–and he certainly used it from the stage yesterday. Sometimes I inwardly flinch, but I'm trying to get over it. Because he brought us 13oo visitors yesterday.
Dance lessons! Photo courtesy John Lehman, DHV volunteer photographer.
As the neighborhood around us changes, we're going to have to rethink museum access. Today, 9,000 people live in the urban core, and 45,000 people live in one of the surrounding neighborhoods. More stunning, there are 5,500 new units under construction right now. Before I ever joined the staff, we offered a neighborhood membership option giving people after-hours access to our grounds. We are the largest green space in downtown, and we're fenced–this is something worth paying for. In the coming months, we're gong to be pushing the neighborhood membership option hard, in a way we never have before.
Photo courtesy Priscilla Killion, DHV volunteer photographer.
As I continue to ponder our options for long-term sustainability, I'm beginning to think that our land might be our greatest asset. We will always be a history museum, first and foremost, but I'm becoming more accepting of the word park. We're not going to tear down our fences. We won't become downtown's largest dog park. As we ponder ways to increase access, we still have to protect our buildings. (as fabulous as Klyde Warren Park is, that can't be our future. Our sweet wooden buildings would die.) But the word park is an important part of our history, and it's an important part of our future as well.
I'm still conflicted about the word park. We are so much more than just a park. But, our historic land, so close to our urban core, certainly makes us special.


New York Fashion Week is important for designers. Not only do they show off their new collection, they have a platform to make statements and change history. This year, designers used the stage to redesign women's fashion. Over-sized coats with feminine details dominated the runway, while classic styles begin to make a comeback.
#1. Marc Jacobs – Marc Jacobs is always a jaw dropper with unique, yet still ready-to-wear, designs. This year, the brand did the unthinkable. No music. No cellphones. Models walked down the runway, and then proceeded to exit outside onto the 36 degrees New York streets. There they took a final pose, proceeded to sit down in metal folding chairs, and whipped out their phones to take selfies. The clothing was able to speak for itself. The ready-to-wear collection was the most instagrammed of all fashion week shows. Well-played, Marc Jacobs.
#2. Calvin Klein Collection – As America's most recognized fashion brand, Calvin Klein is known for their simplicity, denim, and tailoring. The brand's new Belgian chief creator officer, Raf Simons, debuted his first line this past week, wowing the crowds with a blend of feminine detail, bold colors, and tailored lines.
#3. Thom Browne – With an ice skating rink, penguins, and live lamposts, Thom Browne is not a newcomer in the show-stopping department. The brand dressed women in men's suits and large coats with contrasting elements, such as rainbows. The show left everyone in awe by boldly, and successfully, challenging gender stereotypes. This is why fashion and fashion shows matter.
#5. Coach 1941 – We all know Coach for their beautiful leather purses, but the brand's clothing line triumphed this year at NYFW. The collection merged typical masculine pieces with feminine florals and textures. The show itself demonstrated appreciation for the American landscape, with a prairie house at the end of the runway.
# 6. Marchesa – Ethereal, feminine details encompassed this luxurious fashion brand. Established in 2004, this fashion house is best known for their beautiful gowns, including wedding dresses. This year, the brand used Imperial China as inspiration for detailed embroidery and some bolder colors.
#7. Tory Burch -This year, the popular brand enhanced the femininity that has long defined it. The show was held in the Whitney Museum of American Art and was detailed with hearts and hot chocolate. The pieces themselves brought back the classics and were light and floral.
#8. Delpolzo – The collection displayed a strong architectural appreciation. The colors were inspired by a Hungarian painter, József Rippl-Rónai, from the 1890s. Delpolzo is art in design.
#9. Gabriela Hearst – Hearst launched her line 2 years ago, and this was her first formal runway. She focuses on luxury in materials, while her peers tend to focus more on design. Her show was environmentally friendly, she even brought chairs from her house. These differences made her presentation a stand out during NYFW.
#10. Yeezy – Kanye West is no stranger to making statements, and his latest collection did just that. The brand demonstrated how denim can be worn loose and comfortable, while still dressing for purpose. To enhance the importance of each piece, instead of a typical runway, West had a large video screen showing the models walking in the collection.


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OPINIONOPINION,
The threat of ISKP in Afghanistan has been underestimated
The Islamic State's Afghan affiliate could derail Taliban efforts to establish security and stable rule.
Ibrahim Al-Marashi
Ibrahim al-Marashi is an associate professor at the Department of History, California State University, San Marcos.
Published On 27 Aug 202127 Aug 2021
Smoke rises from explosion outside the airport in Kabul on August 26, 2021 [AP/Wali Sabawoon]
On August 26, two suicide bombers killed 72 Afghans and 13 members of the US military at Kabul airport amid evacuation efforts. The Islamic State in Khorasan Province (ISKP), the Afghanistan affiliate of ISIL (ISIS), claimed responsibility for the brutal attack and thus put itself in the international media spotlight.
Although foreign media started paying attention to this group only now, ISKP has been terrorising Afghans since 2015 and it will continue to do so after the August 31 withdrawal of US troops.
There are two aspects of this attack that need to be considered. First, ISKP attacked the airport primarily to discredit its rival, the Taliban, in yet another escalation of the larger conflict between Sunni extremist armed groups. Second, ISKP made it clear that the Taliban will find it hard to keep its promises to ensure the safety and security of civilians, especially women and minorities under its rule.
A conflict between Sunni non-state actors
The emergence of ISIL, the umbrella organisation that includes ISKP, has often been attributed to sectarian dynamics and Sunni-Shia conflicts from the Arab world to Afghanistan and Pakistan.
The problem with blaming violent conflict in this region on tensions between the two sects is that it ignores how the armed group has had a long, bloody legacy of stoking intra-Sunni conflict.
ISIL was formed by defectors from al-Qaeda in 2014 in Syria who then attacked their parent organisation and its Syrian affiliate, Jabhat al-Nusra. ISKP was formed primarily by defectors from the Taliban in both Afghanistan and Pakistan in 2015, who then went on to attack the Afghan branch. In both cases, the defectors considered their former organisations not extreme enough or not committed enough to attack fellow Sunnis, who they considered deviants, or Shia Muslims.
Essentially the conflict between ISIL and its affiliates on one hand, and al-Qaeda and the Taliban on the other, represents an oft-ignored intra-Sunni conflict among extremist groups. Both Syria and Afghanistan are zones of insecurity that have allowed the formation of multiple extremist non-state actors, essentially religious warlords. Since these non-state actors are so close ideologically, their legitimacy is threatened as long as the other rival exists, and thus must be eliminated immediately. Defeating their violent competitors delivers the benefits of monopolising the jihadist narrative as well as gaining new recruits.
This is the conflict ISKP is gearing up for with the Taliban, as the US withdraws. While ISKP numbers have dwindled to 2,000, it can still challenge the legitimacy of the estimated 60,000-strong Taliban. With its forces spread thin across Afghanistan, the Taliban would be particularly vulnerable to violent terror tactics by its splinter.
Anti-Shiaism and the security challenge
The roots of the Taliban in both Afghanistan and Pakistan can be traced to the austere Deobandi school, a South Asian Islamist revivalist movement. In the 1980s, the Sipah-e-Sahaba organisation formed in Pakistan, breaking away from the main Deobandi movement, to focus primarily on an anti-Shia platform. Another group known as Lashkar-e-Jhangvi split from this group in the 1990s, claiming its parent group had deviated from the original anti-Shia platform. Defectors from this group would later join IKSP, attracted by its more brutal anti-Shia campaign.
The brunt of the violence by these groups has been borne by the Hazara, a Shia ethnic minority group, living in Afghanistan and Pakistan. The community has been historically victimised by different Afghan rulers, most famously by Abdurrahman Khan who sought to completely eradicate it in the 1890s.
A century later this community endured violence by the Taliban as it sought to establish its rule over Afghanistan. In 1998, the armed group massacred thousands of Hazaras in Mazar-i-Sharif in retribution for the killing of its fighters following a failed attempt to capture the city the year before.
After ISKP emerged, the Hazara community became one of its main targets. Some of its most brazen attacks include a May 2020 massacre at a maternity hospital in a majority Shia Muslim district of Kabul, killing more than 20 people, including newborn babies and mothers. A year later, in May 2021, it launched an attack at a school in the same district, killing at least 90 people, most of them schoolgirls.
Calling this a "sectarian conflict" would be inaccurate because that would suggest equality between the two sides. It would also obfuscate the racism that along with anti-Shia sentiment drives the attacks on the community, which has long been wrongly considered "non-indigenous" to Afghanistan by other ethnic groups.
This is also reflected in the fact that the US-backed Afghan government never prioritised the safety of the Hazara and in fact, some of its members were known to discriminate against the community.
The Taliban leaders have repeatedly said the rights of minorities and women will be protected. However, whether the leaders can keep their own fighters under control and discipline them when they break their orders remains to be seen.
What is certain is that the Taliban will find it extremely difficult to rein in ISKP and eliminate its appeal among more extreme elements of the Afghan society and its own ranks.
As for the US, the bloody attack on August 26 will compel the Biden administration to retaliate, which would ultimately complicate the plans for a full military withdrawal and potentially even harm relations with the Taliban itself.
The views expressed in this article are the author's own and do not necessarily reflect Al Jazeera's editorial stance.
Ibrahim al-Marashi is an associate professor at the Department of History, California State University, San Marcos. He is the co-author of the forthcoming The Modern History of Iraq, 4th edition.
The collapse of Afghan military: We've seen this movie before
Pope Francis's visit to Iraq: Beyond the symbolism
Soleimani's death will give Iran renewed legitimacy
The day after al-Baghdadi's death

redpajama_set_name: RedPajamaCommonCrawl


The 2010 Buick LaCrosse sedan made its debut a year ago, and it's been a huge hit. Kelsey Mays reviewed the whole LaCrosse lineup last year, including CX and CXL trims with the 3.0-liter V-6, and the top CXS trim level with the 3.6-liter V-6. Now, Buick has added a four-cylinder version of the CX to lower the price a bit and boost gas mileage. (See all versions compared.) All these cars are 2010 models, so Kelsey's review remains a comprehensive evaluation. I'll concentrate on the new four-cylinder's performance and some new observations.
Overall, the four-cylinder LaCrosse will further expand the model's considerable appeal, but its modest power means it's unlikely to become a significant part of the mix.
In terms of base price, the four-cylinder saves you only $840 over the V-6-powered CX, but the mileage bump is a more significant 2 mpg in the city (to 19 mpg), 4 mpg on the highway (to 30 mpg) and a combined 2 mpg improvement in mixed driving (to 23 mpg).


In this video, Hans W1JSB, shows us his newly designed and highly anticipated Elecraft KX2 QRP Upgrade Kit. The kit is self-contained for rapid deployment and ease of use.
The Elecraft KX2 QRP Upgrade Kit is super compact and lightweight, a must have for QRP Operators, Campers, Hikers, or Ham Radio Preppers.
Available May, 2018 from RadioSet-GO.
If you found this video useful, please consider sharing it with others by pinning the image below. Thanks!


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12, Some Streeet, 12550 New York, USA
silverscreen@edge-themes.com
Danny Holguin
Short Films & Documentaries
Documental "Destinos Interrumpidos" / "Interrupted Destinies" Documentary
Documental "La Boquilla, Mi Paraiso" / "La Boquilla, My Paradise" Documentary
Cortometraje "Mani Cura" / "Mani Cura" Short Film
Documental "El Mito del Cambio" / "The Myth of Change" Documentary
Documental "El despertar de las hadas" / "The awakening of the fairies" Documentary
Documental "La Virgen Puta" / "The Virgin Whore" Documentary
Corto Documental "Freddy" / "Freddy" Documentary Short
Experimental short "One last Kiss" / "Un ultimo beso" corto experimental
Danny's Photography
Danny's Storyboards
Danny's Cartoons
DHO STUDIOS
WELCOME TO DHO STUDIOS LLC
(DANIEL HOLGUIN OLIER STUDIOS)
DHO Studios LLC is the film production firm of award-winning filmmaker and visual artist Danny Holguin. This firm has produced all types of audio visual content with special focus on storytelling with deep impact. Our projects have garnished important international awards and have travelled multiple film festivals around the globe, along with international press.
DHO Studios LLC es la firma de producción del premiado cineasta y artista visual Danny Holguin. Esta firma ha producido todo tipo de contenido con un enfoque especial en ilustrar historias de impacto profundo. Nuestros proyectos han sido galardonados con premios y han recorrido importantes festivales de cine alrededor del planeta, ademas de prensa internacional.
Danny and Juan Carlos directed and produced my first music video. I wanted to work with Danny for a long time, I had offers from other directors but Danny ended up being my best option. Danny and Juan are not only the best at what they do, to work with them it's just fun. Danny's creative vibe and professionalism is mixed with his humility and sense and humor that made me feel at ease and comfortable in front of cameras. The final product is just amazing, it clearly shows their great directing skills. I would definitely work with Danny and Juan in my up coming music videos.
Angela Paniza	- Recording artist/composer | www.angelapaniza.com
I have been friends with and worked with Danny Holguin for many years in the entertainment business; His impeccable creative talent always produced high quality work in his video and film productions that have won awards worldwide. Mr. Holguin truly has perfected his craft as globally renowned filmmaker and talented illustrator over the years; Danny was extremely reliable, incredibly imaginative and exceptionally collaborative, when working with one of the artists I managed, having created videos of her live music performances. He was very resourceful and attentive to detail on every set. His most recent projects were filmed between the USA, Colombia, Germany and Switzerland. Danny Holguin brings magic to the table by staying true to every project he works on. Danny's ingenuity, high work ethic and brilliant artistic works will be an incredible asset to any company he works for and any festival or event his works are placed in!
Nicolete Fontaine	- Media agent
Destinos Interrumpidos (Interrupted Destiny) is an amazing documentary film that would keep you glued to your seat till the end. I first saw this film at a film festival, where the powerful narrative of the film made the audience go "wow". Although there have been movies or TV shows about being switched at birth, they compare nothing to Destinos Interrupidos. The story unfolds in the beautiful, coastal town of Cartagena, Colombia where two kids are accidentally switched at birth by the hospital staff. The boy born to a well to do family is passed onto a family not so fortunate in life's luxuries. And the boy from the ordinary family is given to the rich family. Although, the families live only about 20 minutes apart, the two boys grow up without knowing the trick destiny played on them: until age 26 when they meet face to face for the first time. This documentary is a roller coaster of emotions, surprises, tears and lost moments and memories. The filmmakers have done a marvelous job in telling the story of the two families with sensitivity and objectivity without losing the powerful narrative that underlies this film. The documentary features superb cinematography, capturing the beauty of Cartagena and subtle nuances of the environments in which the two young men grow up. Combined that with flawless editing and perfect music, you'll find yourself watching this movie more than once! I highly recommend this film to anyone.
Tas Salini	- Producer, Writer, Director, Professor of Media Arts
Whenever I need to partner up with fellow filmmakers, there is no doubt in my mind that Danny and Juan Carlos are the guys to call, they work with a great sense of professionalism from start to finish. Their creative input in pre-production, production and post, makes every job interesting and fun to work in. I admire how Danny has the ability to illustrate storyboards and then we all see the final image captured on Film.
Stephen Brevig	- Cinematographer | "Premium Image Studios"
DHO Studios along with my company produced my first feature full length film, it was a lot of work, they worked with a sense of urgency and passion that captivated me since day one. I have known Danny Holguin for years. He has worked on my other projects as well. Danny has worked with me as a producer and a Director of Photography. Danny helped with storyboard illustration, coordinated all crew, locations, equipment, shot lists, actors and most other areas of the production. Danny also has a creative and unique method of filming. He takes ample time to set-up and shoot each scene. I would work with Danny again and welcome him to work on other projects with me.
Justin Routt	- Director/Producer | "Birch Creek films"
Copyright © DHO Studios, LLC.
DannyHolguinOlier@dhostudios.com
Copyright © DHO Studios, LLC


Finally the wait is over. iOS 12 beta has been released for iPhone X, 8 Plus/8, 7 Plus, 6S, SE, iPad Air and Mini. Check out more details about the latest iOS 12 released by Apple.
iOS is the operating system of iPhone and iPads. Apple release major update for its iOS each year in June and same is done this year in WWDC. Users are excited and want to get their hands on latest iOS 12 to try out the new features.
Apple followed its tradition of adding few new features to new iOS. This year, with iOS 12, Apple followed same trend.
The final version of iOS 12 will be launched along with release of new iPhone in September, this year.
The most important feature added to iOS 12 by Apple are fixing the performance issues on iPhone X. We have seen lot of problems with iOS 11 and iPhone X.
Since this is beta version of iOS 12, so lot of bugs are expected in this version. Moreover, users are required to have UDID and registered Apple's developer accounts in order to install and activate iOS 12 beta using its ipsw files.
Once you have downloaded the correct iOS 12 beta .ipsw file for your iPhone or iPad, it is time to proceed with its installation using iTunes.
Let us know if you have any question related to iOS 12 beta ipsw for your iPhone X, 8 Plus, 6S/SE, iPad Air or Mini. Meanwhile, do share your experience of running iOS 12 beta on your iDevice.


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CCU professor Hills readies for Russian assignment by Mona Prufer
'Discovering the Dürer Cypher' opens at the Bryan Gallery by Jim Arendt
Faculty embrace new sports mentorship program by Mona Prufer
Foreign language professor Matthieu Chan Tsin played college football 10 years ago.
Faculty embrace new sports mentorship program
by Mona Prufer
During his college days some 20 years ago, Matthieu Chan Tsin played football in the U.S., France and the U.K. It was a challenging time, and he never felt that the faculty understood the difficult balancing act of a student-athlete trying to make good grades while keeping up a grueling practice schedule.
So Chan Tsin, chair of CCU's Department of World Languages and Culture, signed up to be in the Faculty Associates Program for the second year. It's a pilot program that pairs a faculty member with a sport team; Chan Tsin's team is football.
"This is an opportunity for me to rectify something I had noticed some years ago," says Chan Tsin, who hangs out with the team and helps with drills at practice. "It's important to give back to a sport that gave me so much, things like the importance of being a good team player and not just going off on your own."
The Faculty Associates Program is an athletic program designed to engage CCU faculty with individual sport players by connecting volunteers with a team. Sharon Thompson, the faculty athletic representative, started the program after learning about a similar program on another campus. In its second year of existence, the program now has eight faculty members paired with seven teams. (Football, because of the size of the team with around 100 players, has two faculty associates.)
Dennis Edwards, professor of economics, and Chan Tsin are assigned to the football team. Colleen McGlone, who is also in her second year in the program and the only woman faculty associate, is assigned to women's basketball. Brian Bunton, assistant professor of chemistry/physics, has baseball; Greg Geer, assistant professor of educational leadership, has women's lacrosse; Paul Richardson, associate professor of biochemistry, has women's soccer; Don Rockey, associate professor of recreation and sport science, has men's basketball; and Yoav Wachsman, associate professor of economics, is assigned to women's volleyball.
Edwards, who "played football in the fourth grade for three weeks," is a huge sports fan who has Cardinals World Series (2006) and LSU Championship (2007) banners hanging in his office. "It was described to me as a mentoring role," says Edwards. "I am 39 and have had my share of mistakes along the way. If I can help anybody avoid some of my mistakes, then I want to do that. This combines my love of sports with my desire to make a difference."
Volunteer faculty members serve as academic mentor, team supporter and as liaison to other faculty and administrators. They attend team practices, stand with the team on the sidelines at games and travel to at least one competition with the team.
Yoav Wachsman loves the sport of volleyball and was looking for a way to get more personally involved with students – the faculty associates program was perfect for him. He sits in on the team meeting at practices, and assists a bit at practice when needed.
"At first the team didn't know what to do with me," says Wachsman, who traveled on the bus with the 12 volleyball players to Greenville for an invitational meet. "Now they ask me when I am coming to practice. They know I am here for them."
On the recent trip, Wachsman was struck by the intensity of the players' roller coaster emotions – very elated when winning, very down when losing. "It is very intense even for me now," he says. "It is heartbreaking when they lose. I tell them to play with passion, not fear." The program, he says, is all about supporting the students.
"The University wants to show athletes there's someone there to support them on a personal basis," he says. "It's not just about winning and losing. It's about being successful."
Colleen McGlone sees real value in a program that gives student-athletes a "more neutral" person to talk to who is not a coach or a professor in their field. "We are not there to change grades or drop classes," she says. "We are there to strengthen the bond between the student and the faculty."
McGlone, who would like to see more female faculty volunteers, says she has talked with student players about everything from stress management to study habits to what happens after graduation. "I would love to see all sports covered," she says. "And I would like to see people who are not into athletics get involved to gain that perspective."
Paul Richardson, who is assigned to women's soccer, brings his two little girls to the home games.
"I was looking for some ways to be more involved with my daughters," says Richardson. "I don't need any more committees to serve on, but this seemed to be a good way to be involved at work and at the same time spend quality time with my girls. I also wanted to learn more about athletics."
Ella, 3, and Caroline, 6, love going to the games and have even helped lead cheers toward the end of a game. They've been to four or five home games so far, but Richardson, who was a varsity athlete on the college swimming team, hopes watching women's soccer will positively impact his children.
"These (soccer) girls could be an inspiration for my girls," says Richardson, who so far has not noticed any athletic tendencies in his young children, though the older one takes ballet. "We like for them to have different experiences, and this has been a positive one."
Article Photos


"The students were all dressed up; the boys were wearing ties!" Susan Parker was enthusing over the reception she and her husband, Don, as Grandpals, were given June 19 at Spencer Avenue Elementary School. This is a school for gifted children and it is where the Grandpals program was re-launched in April of this year.
The gala for which Ms. Parker had such praise was the wrap-up event of six weeks of meetings between the students from grades four and five. The event was worth the fuss for the production that the students put together for each of their short term mentors was quite overwhelming.
Each student prepared a presentation for his or her individual grandpal with so many of the details from the conversations they had shared over the weekly meetings. There was station to review each relationship.
"They each had their own laptop, with pictures going through. We all went around to all the exhibits," she told the Citizen.
The students thanked their grandpals for listening to them and introducing them to another generation.
The gala was very well attended, not only by the families of the students, their own grandparents and parents, but also the principal of the school and a superintendent from the Upper Grand District School Board.
The grandpals program was introduced at in this area at Montgomery Public School but was apparently dropped from lack of seniors to participate. With a renewed interest in the idea, there has been good response to the latest round of junior-senior talks, resulting in real growth and benefit. Let it be clear, everyone has learned and benefitted, children and adults all.
With the very satisfactory completion of this year's program, the coordinator, Elisabeth Mangos, is deeply impressed with the level of conversations and thinking the program encourages, starting with a list of question to be discussed by the young and older. What is a citizen? What was a difficult time in your life and how did you deal with it? What were some of the good times? They discussed all manner of ideas. One conversation lead to other ideas.
It came about that the discussion delved into family history and, for her own information, as well as providing a thumb sketch of her own, Mrs. Parker discovered that her great grandmother was adopted and was actually born in Orangeville.
"So, I have a historical connection to this town where I now live," said she, still amazed by the discovery.
Interestingly, Mr. and Mrs. Parker have taken separate stances on continuing to be a grandpal. For Don Parker, it was entirely rewarding in another way, in spite of their having several of their own grandchildren.
Retired from the computer business, Mr. Parker has, nevertheless, kept up date and the three boys with whom he was a grandpal, were enthralled at an older person's very modern knowledge. They were his youthful colleagues and he is prepared to meet others. Thus, he plans to offer himself as a grandpal again.
Mrs. Parker, on the other hand, has a specific activity always scheduled on the same day of the week as her obligation at the school. So, while she was delighted to have walked the path with her students, she feels that she would like to return to her normal routine.
It was good to be able to share that valuable knowledge.