The mesolimbic dopaminergic system has been implicated in mediating the motivational effects of oploids and other drugs of abuse. The site of action of opioids within this system and the role of endogenous opioid peptides in modulating dopamine activity therein remain unknown. Employing the technique of in vivo microdialysis and the administration of highly selective opioid ligands, the present study demonstrates the existence of tonically active and functionally opposing it and K opioid systems that regulate dopamine release in the nucleus accumbens, the major terminal area of A10 dopaminergic neurons. Thus, stimulation of J-type receptors in the ventral tegmental area, the site of origin of A10 dopminergic neurons, increases dopamine release whereas the selective blockade of this opioid receptor type results in a significant decrease in basal dopamine release. In contrast, stimulation of K-type receptors within the nucleus accumbens decreases dopamine release whereas their selective blockade markedly increases basal dopamine release. These data show that tonic activation of pA and ic receptors is required for the maintenance of basal dopamine release in the nucleus accumbens. In view of the postulated role of the mesolimbic system in the mediation of drug-induced alterations in mood and affect, such findings may have implications for the treatment of opiate dependence and affective disorders.There is evidence that exogenous opioids can influence the activity of mesolimbic dopaminergic neurons and it has been postulated that such actions underlie the motivational (1, 2) and locomotor effects (3, 4) of these agents, as well as the development of various aspects of opiate dependence (5-7).The behavioral effects of opioids differ depending on the opioid receptor type with which they interact. Thus, systemically applied P-receptor agonists function as positive reinforcers and increase locomotor activity. In contrast, K-receptor agonists have aversive and sedating effects (8, 9). Opposing effects of these agents are also observed at the neurochemical level within the mesolimbic dopaminergic system: A agonists increase, whereas K agonists decrease, dopamine release in the nucleus accumbens (10, 11), the major terminal projection site of mesolimbic dopaminergic neurons. The behavioral effects of opioids noted above are abolished following 6-hydroxydopamine lesions of the mesolimbic system or selective blockade of the dopamine receptors therein (2, 4, 9, 12, 13), suggesting that mesolimbic dopaminergic neurons are necessary for the expression of these actions. Specifically, it has been hypothesized that the opposing effects of A and K agonists on mesolimbic dopaminergic release underlie their different effects on motivation and motor behavior.Neither the site of action of exogenous opioid agonists within this system in affecting dopamine release nor the role of endogenous opioid systems in regulating mesolimbic dopaminergic system activity is known. The latter issue has, until recently, been complicated by the ...
The kappa opioid agonists are analgesics that seem to be free of undesired morphine-like effects. Their dysphoric actions observed with the kappa agonist cyclazocine are thought to be mediated by an action at sigma-phencyclidine receptors. The benzomorphan kappa agonist MR 2033 is inactive at sigma-phencyclidine receptors. In male subjects, the opiate-active (-)-isomer, but not the (+)-isomer, elicited dose-dependent dysphoric and psychotomimetic effects that were antagonized by naloxone. Thus, kappa opiate receptors seem to mediate psychotomimetic effects. In view of the euphorigenic properties of mu agonists, our results imply the existence of opposed opioid systems affecting emotional and perceptual experiences.
Alcohol exerts numerous pharmacological effects through its interaction with various neurotransmitters and neuromodulators. Among the latter, the endogenous opioids play a key role in the rewarding (addictive) properties of ethanol. Three types of opioid receptors (mu, delta and kappa) represent the respective targets of the major opioid peptides (beta-endorphin, enkephalins and dynorphins, respectively). The rewarding (reinforcing) properties of mu- and delta-receptor ligands are brought by activation of the mesolimbic dopamine system which ascends from the ventral tegmentum of the midbrain (VTA) to rostral structures; of these, the nucleus accumbens (NAC) is of particular importance in drug addiction. In contrast, dysphoria results from activation of kappa-receptors. The neurochemical manifestations of these opposing effects are, respectively, increases and decreases in dopamine release in the NAC. Several lines of evidence indicate that alcohol interferes with endogenous opioid mechanisms which are closely linked with dopamine transmission in the mesolimbic pathway. The view that condensation products of dopamine and alcohol-derived aldehyde (tetrahydroisoquinolines) play a role remains controversial. There is, however, much information on the direct (acute and chronic) effects of alcohol on the binding properties of opioid receptors, as well as modulation of opioid peptide synthesis and secretion (e.g. a suggested increase in beta-endorphin release). In view of the reinforcing properties of alcohol, it is relevant to consider behavioural studies involving alcohol self-administration in rodents and primates. Low doses of morphine have been found to increase, and higher doses of the opiate to decrease, alcohol consumption. Conversely, opioid antagonists such as naloxone and naltrexone (which bind to non-selectively opioid receptors) have been shown to decrease alcohol consumption under various experimental conditions. Similar results have been reported when selective mu- or delta-receptor antagonists are administered. Results obtained in genetic models of high preference for alcohol also support the view that alcohol intake depends on the activity of the endogenous opioid reward system and that alcohol consumption may serve to compensate for inherent deficits in this system. One hypothetical model proposes that reward results from activation of mu-opioid receptors in the VTA and/or delta-receptor in the NAC; both these nuclei are targets of endogenous beta-endorphin. It is suggested that alcohol interferes with this reward pathway either directly or indirectly. The available experimental data accord well with those obtained from clinical studies which opioid antagonists have been used to prevent relapse in alcoholics. Conceptual considerations concerning communalities between various forms of addictions are also discussed in this review.
According to classical models of drugreceptor interactions, competitive antagonists share with agonists the ability to bind to a common site on the receptor molecule. However, they are different from agonists, as they cannot trigger the "stimulus" that leads to biological responses-i.e., they lack intrinsic activity. For those receptors whose signals are transduced to effector systems by GTPbinding regulatory proteins (G proteins), a mechanistic equivalent of such a stimulus is an increased ability of agonist-bound receptor to accelerate nucleotide exchange and thus GTPase activity on the G-protein molecule. Here we show that for a member of this family of receptors (6 opioid receptors in membranes of NG108-15 neuroblastoma-glioma cells), two types of competitive antagonists can be distinguished. One type has no intrinsic activity, since it neither stimulates nor inhibits the GTPase activity of G proteins and its apparent ainmity for the receptor is not altered by pertussis toxin-mediated uncoupling of receptor and G protein. The second type, however, can inhibit GTPase and thus exhibits negative intrinsic activity; its affinity for receptors is increased following uncoupling from G proteins. The existence of antagonists with negative intrinsic activity may be a general feature of several classes of neurotransmitters or hormone receptors and calls for a reevaluation of biological effects produced by competitive antagonists.Although ,u and 8 opioid receptors can be clearly distinguished on a pharmacological basis (1), recent evidence (2, 3) indicates that these two types of receptors share the ability to interact with GTP-binding regulatory proteins (G proteins). In this respect, they belong to a large family of hormone and neurotransmitter receptors whose signals are transmitted to enzymes and ion channels across plasma membranes by intervening G proteins (reviews in refs. 4-6). Activation of one or more G proteins, which results in increase of GTPase activity, is the first detectable biochemical event that follows recognition of this group of receptors by agonists, regardless of the sort of signal that is actually propagated to effector molecules (5, 6). Receptor-mediated activation of G proteins involves the establishment of a ternary complex between ligand-occupied receptor and G protein, as suggested long before the isolation of G proteins. The findings (i) that guanine nucleotides exert negative heterotropic effects on the affinity of the receptor (7) only when the receptor is occupied by an agonist (8, 9), (ii) that a receptor prelabeled by agonists can be solubilized in a higher molecular weight form than when prelabeled by antagonists (10), and (iii) that agonists but not antagonists display complex binding isotherms in the absence of guanine nucleotides (11) liposomes (12, 13). Accordingly, the intrinsic activities of receptor ligands represent their ability to stabilize the ternary complex and range from null values for antagonists, which passively occupy the binding site, to various degrees of...
An involvement of the mesolimbic dopamine (DA) system in mediating the motivational effects of opioids has been suggested. Accordingly, the present study employed the technique of in vivo microdialysis to examine the effects of selective mu-, delta-, and kappa- opioids on DA release in the nucleus accumbens (NAC) of anesthetized rats. Microdialysis probes were inserted into the NAC and perfusates were analyzed for DA and its metabolites, dihydroxyphenylacetic acid (DO-PAC) and homovanillic acid (HVA), using a reverse-phase HPLC system with electrochemical detection for separation and quantification. Intracerebroventricular (i.c.v.) administration of selective mu-opioid [D-Ala2, N-methyl-Phe4, Gly5-ol]-enkephalin (DAMGO) or delta-opioid [D-Pen2, D-Pen5]-enkephalin (DPDPE) agonists, at doses that function as positive reinforcers in rats, resulted in an immediate and significant increase in extracellular DA. DOPAC and HVA levels were also significantly increased. The effects of DAMGO were blocked by the selective mu-antagonist D-Pen-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP) whereas those of DPDPE were blocked by the delta-antagonist allyl2-Tyr-Aib-Aib-Phe-Leu-OH (ICI 174,864). In contrast to mu- and delta-agonists, the kappa-agonist N-CH3-Tyr-Gly-Gly-Phe-Leu-Arg-N-CH3-Arg-D-Leu-NHC2H5 (E-2078), a dynorphin analog that produces aversive states, decreased DA release in a biphasic manner. Norbinaltorphimine, a selective kappa-antagonist, could block this effect. These results demonstrate that mu-, delta-, and kappa-opioid agonists differentially affect DA release in the NAC and this action is centrally mediated.
The reinforcing properties of various opioid agonists acting preferentially on the kappa and mu opioid receptors were assessed using taste and place preference conditioning procedures. Kappa receptor agonists produced conditioned aversions. Taste aversions were produced by all of the drugs used, including racemic mixtures of ethylketazocine, tifluadom, and U50-488, and active isomers (+)-tifluadom, (-)-bremazocine, and Mr 2034; corresponding inactive isomers either produced no effect of were less potent. Place aversions were produced by U50-488 and (-)-bremazocine, but not (+)-bremazocine or any of the other kappa receptor agonists tested with the taste procedure. The mu agonists produced predominantly conditioned preferences. Place preferences were produced by morphine, fentanyl and sufentanil. Taste preferences were produced by low doses of these substances; at higher doses the taste preferences were absent or replaced by aversions. Finally, with naloxone and lithium chloride it was shown that the taste procedure was more sensitive to punishing effects than the place procedure. It is concluded that kappa and mu opioid receptor agonists are effective unconditioned stimuli. From the lower portions of the dose response curves it is further concluded that activation of kappa opioid receptors has aversive properties and activation of mu receptors appetitive reinforcing properties. The findings are also discussed with regard to the prevailing notions of taste conditioning with opiates, and the reinforcing properties of activity of the endogenous opioid peptide systems.
Low doses of intraarticular morphine can significantly reduce pain after knee surgery through an action specific to local opioid receptors that reaches its maximal effect three to six hours after injection.
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