It is, however, important to note that all classes of opioid receptors share key similarities. First, the receptors have a common general structure. Cloning demonstrates that the receptors are usually G protein-linked receptors imbedded in the plasma membrane of neurons (Satoh and Minami, 1995). Once the receptors are bound, a portion of the G protein is activated, which allows it to diffuse within the plasma membrane. The G protein moves within the membrane until it reaches its target, which is either an enzyme or an ion channel. Most often, the targets alter protein phosphorylation and/or gene transcription, which alter the short-term and long-term activity of the neuron, respectively.
Although opioids usually activate G proteins, it was recently demonstrated that opioids occasionally act independently of G proteins. A key study found that DAMGO, a selective mu receptor agonist, modulates calcium-dependent potassium channels independently of G proteins in bovine adrenal medullary chromaffin cells (Twitchell and Rane, 1994). The finding further highlights the complexity of the opioid system.A second similarity is that activation any type of opioid receptors inhibits adenylate cyclase (Childers, 1991), which is an enzyme responsible for catalyzing numerous chemical reactions in neurons. Activation of each type of receptor appears to shares a common property, which allows them to alter adenylate cyclase activity. The common property/ies may explain why different types of opioid receptors occasionally have the same effect on a neuron. Even though opioid receptors share the ability to inhibit adenylate cyclase, each receptor subtype has unique series of effects that can not be produced by any other type of opioid receptor.
A final similarity is that all types of opioid receptors are present both presynaptically and postsynaptically in neurons (review in Simon, 1991). When acting at presynaptic receptors, the peptides function as neuromodulators affecting the release of neurotransmitters. At postsynaptic receptors, the peptides act as neurotransmitters by directly altering membrane potentials. The overall effect of opioids on a particular tissue depends upon the concentration and location of particular opioid receptors in the area.
Clinical and recreational opioid use is limited by the development of tolerance and dependence. Tolerance can be defined as the decreased potency of a drug, such that progressively larger doses must be used to achieve the same effect. Dependence, which is closely associated with tolerance, involves a continued need for opioid administration in order to prevent withdrawal symptoms. These symptoms include nausea, gastrointestinal disturbances, chills, and a general flu-like state in humans (Jaffe, 1980) and ptosis (drooping eyelid), teeth chattering, jumping, irritability, wet dog shakes, and diarrhea in animals (Wei et al., 1973). Lesion studies indicate that no single brain structure is responsible for the withdrawal symptoms (Adler et al., 1978).The opioid system is connected with most neurotransmitter networks in the body. The interaction between the opioids and the dopaminergic system appears to be involved in addiction, tolerance, and withdrawal symptoms. The relevant interaction appears to occur along the mesolimbic projection, particularly in the ventral tegmental area (VTA) and nucleus accumbens (NA).
It has been further demonstrated that opiates applied to the VTA prompt animals to engage in behaviors increases dopamine activity. Specifically, VTA morphine causes rats to self-administer cocaine (Stewart, 1984), which is known to potentate DA activity. The study suggests that dopamine further augments the rewarding properties of opioids in the VTA. In fact, morphine enhances the firing frequency of mesolimbic DA neurons projecting from the VTA (Matthews and German, 1984), which provides firm evidence that opioids have an excitatory affect on dopamine. Not only do opioids have an excitatory effect on dopamine; the effects of opioids seem to be contingent upon dopamine activation. Dopamine antagonists, molecules that bind to the receptor and prevent it from being activated, block the effect of opioids by halting morphine-induced activities (Iwamoto, 1981).
Although dopamine excitation likely increases the rewarding effect of opioids, it appears that reinforcement is not contingent upon dopamine activation. A key study found that heroine self-administration continues after disruption of DA innervation in NA, which suggests that rewarding effects of opiates are only partially contingent on DA release in the NA (Koob and Bloom, 1988). The finding is consistent with the discovery that animals will self-administer opioids in the NA (Olds, 1982), which suggests that opioid activity in the NA has a rewarding effect independent of neurons from the VTA.
It is important to note that the animals will modify their behavior more to obtain opioids in the VTA (Olds, 1982), which suggests that the VTA activation produces a more rewarding effect than NA activation.
Another line of research suggests that dopaminergic input is not necessary for opioid reward. 6-OHDA lesions in NA, which specifically destroy dopaminergic neurons, did not effect lever press linked to opioid reward (Robbins et al., 1989).
Yet, it does appears that dopamine has an excitatory effect on opioid-induced reward. Dopamine antagonists slow response speed in reinforced tasks, but do not eliminate the response all together (Evenden and Robbins, 1983). A recent study also found potentiation of opioid activity by dopamine agonists, while dopamine antagonists inhibit opioid activity (Cook et al., 1999). On a cellular level, dopamine administration in NA tissue elicits changes in electrical activity when cell slices are placed in a test tube mimicking the brain's environment (Pennartz et al., 1992). In reviewing the body of research, dopamine seems to enhance the actions of opioids on reward in the NA, but does not appear to be required for reinforcement.
It is interesting to note that opioid and dopamine agonists alike, both substances associated with addiction, depress overall excitation in the NA (Pennartz et al., 1992). Yet, muscarinic agonists decrease excitation in the NA without altering addiction (Pennartz and Lopes da Silva, 1994).
The NA appears to not only be involved in opioid withdrawal, it also appears to play a role in opioid tolerance. A study examining NA dopamine concentrations found that concentrations are higher in tolerant rats than in controls (Johnson and Glick, 1992). Researchers have yet to demonstrate how the change in dopamine concentrations, associated with a change in reinforcement, plays a role in opioid tolerance.
Childers, S.R., Opioid receptor-coupled second messenger systems., Life Science, 48: 1991-2003, 1991.
Cook, C.D., Rodefer, J.S., and Picker, M.J., Selective attenuation of the antinociceptive effects of mu opioids by the putative dopamine D3 agonist 7-OH-DPAT, Pscyhopharmacol., 144: 239-247, 1999.
Dhawan, B.N., Cesselin, F., Raghubir, R., Reisine, T., Bradley, P.B., Portoghese, P.S., and Hamon, M., International union of pharmacology classification of opioid receptors, Pharmac. Rev., 48: 567-591, 1996.
Evenden, J.L. and Robbins, T.W., Dissociable effects of d-amphetamine, chlordiazepoxide and alpha-flupentixol on choice and rate measures of reinforcement in the rat, Psychopharmacol., 79: 180-186, 1983.
DiChiata, G. and North, R.A., Neurobiology of opiate abuse, Trends in Pharmacol. Sci., 13: 185-193, 1992.
Graybiel, A.M., Moratalla, R., Robertson, H.A., Amphetamine and cocaine induce drug-specific activation of the c-fos gene in striosome-matrix compartments and limbic subdivisions of the striatum. Proc. Natn. Acad. Sci. USA, 87: 6912-6916.
Iwamoto, E.T., Locomotor activity and antinociception after potative mu, kappa, and sigma opioid agonists in the rat: Influence of dopaminergic agonists and antagonists, J. Pharmac. Exp. Ther., 217: 451-460, 1981.
Jaffe, J.H., Goodman and GilmanŐs the Pharmacological Basis of Therapeutics. In Drug Addiction and Drug Abuse (eds Goodman, L.S., Gilman, A., Mayer, S.E., and Melmono, K.L.), 545-546, MacMillan, New York, 1980.
Johnson, D.W., and Glick, S.D., Dopamine release and metabolism in NA and striatum of morphine-tolerant and nontolerant rats, Pharmacol. Biochem. and Behav., 46: 341-347, 1993.
Koob, G.F. and Bloom, F.E., Cellular and molecular mechanisms of drug abuse, Science, 242: 715-723, 1988.
Koob, G.F., Drugs of abuse: anatomy, pharmacology, and function of reward pathways, Trends in Pharmacol. Sci., 13: 177-184.
Matthews, R.T. and German, D.C., Electrophysiological evidence for excitation of rat VTA dopamine neurons by morphine, Neurosci., 11: 617-625, 1984.
Mavaridis, M. and Besson, M.J., Dopamine-opiate interaction in the regulation of neostriatal and pallidal neuronal activity as assessed by opioid precursor peptides and glutamate decarboxylase messenger RNA expression, Neurosci., 92: 945-966, 1999.
Olds, M.E., Reinforcing effects of morphine in the nucleus accumbens, Brain Res., 237: 429-440, 1982.
Phillips, A.C., and LePiane, E.G., Pharmacol. Biochem. Behav., 12:965-968, 1980.
Pennartz, C.M.A., Dolleman-van Der Weel, M.J., Kitai, S.T., and Lopes da Silva, F.H., Presynaptic dopamine D1 receptors attenuate excitatory and inhibitory limbic inputs to the shell region of the rat NA studies in vitro, J . Neurophysiol., 67: 1325-1334, 1992.
Pennartz, C.M.A. and Lopes da Silva, F.H., Muscarinic modulation of synaptic transmission in rat NA slices is frequency-dependent, Brain Res., 1994.
Robbins, T.W., Cador, M., Taylor, J.R., Everitt, B.J., Limbic-striatal interactions in reward-related processes, Neurosci. Biobehav. Rev., 155-162.
Satoh, M. and Minami, M., Molecular pharmacology of the opioid receptors, Pharmacol. Ther., 68: 343-364, 1995.
Simon, E.J., Opioid receptors and endogenous opioid peptides, Medicinal Res. Rev., 11: 357-374, 1991.
Stewart, J., Reinstatement of heroin and cocaine self-administration behavior in the rat by intracerebral application of morphine in the ventral tegmental area, Pharmacol. Biochem. Behav., 20: 917-923, 1984.
Stinus, L., LeMoal, M., Koob, G.F., NA and amygdala are possible substrates for the aversive stimulus effects of opiate withdrawal, Neurosci., 37: 767-773, 1990.
Twitchell, W.A. and Rand, S.G., Nucleotide-independent modulation of a calcium-dependant potassium channel current by a mu-type opioid receptor, Mol. Pharmacol., 49: 793-798, 1994.
Wei, E., Loh, H.H., and Way, E.L., Quantitative aspects of precipitated abstinence in morphine-dependant rats, J. Pharmac. Exp. Ther., 184: 398-403, 1973.
Welzl, H., Kuhn, G., and Huston, J.P., Self-administration of small amounts of morphine through glass micropipettes into the ventral tegmental area of the rat. Neuropharmac., 28: 1017-1023, 1989.
Westernik, B.H. and Korf, J., Regional rat brain levels of dihydrophenylacetic acid and homovanillic acid: Concurrent fluoimetric measurement and influence of drugs, Eur. J. Pharmacol., 38: 281-291, 1976.