Involvement of mesolimbic kappa-opioid systems in the discriminative stimulus effects of morphine.
The neuroanatomical basis of opiate addiction has been studied using a variety of behavioural techniques. The aim of the present study was to investigate the role of mesolimbic opioid systems, in particular kappa-opioid systems, in the expression of the discriminative stimulus effects of abused drugs. Rats were trained to discriminate morphine (3.0 mg/kg s.c.) from saline under a fixed ratio schedule of food reinforcement. Once rats had acquired the discrimination, a randomized sequence of different doses of the highly selective kappa-opioid receptor agonist U69593 (0.02-0.16 mg/kg s.c.) was given 20 min prior to a systemic morphine injection. U69593 dose-dependently blocked the morphine discrimination. It is important to note that U69593 at these doses failed to generalize to the systemic morphine cue. The site of action by U69593 (0.02-0.16 microgram) was examined by microinjecting discrete amounts into target brain regions. Intra-nucleus accumbens injections of U69593 dose-dependently blocked the systemic morphine cue, whereas, U69593 failed to generalize to the discriminative stimulus. The same doses did not affect morphine discrimination after intra-ventral tegmental area or striatum injections. Besides the rewarding effects of drugs of abuse, the discriminative stimulus properties of these agents are seen as a major factor in drug seeking behaviours. The present study shows that the discriminative effects of morphine, a measure of the subjective effects of this drug can be blocked by the activation of kappa-opioid receptors located in the nucleus accumbens. In view of these findings which show that the activity of endogenous potassium-opioid systems (dynorphin) may serve as physiological antagonists to counteract the effects of morphine, potassium-agonists therefore may be useful in the treatment of opioid addictions.
Spanagel
R
R
Department of Neuroendocrinology, Max Planck Institute of Psychiatry, Clinical Institute, Munich, Germany.
Shoaib
M
M
D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D044482:Benzeneacetamides; D001931:Brain Mapping; D003463:Cues; D004193:Discrimination Learning / Q000187:drug effects; D004192:Discrimination, Psychological / Q000187:drug effects / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D007279:Injections, Subcutaneous; D008032:Limbic System / Q000502:physiology*; D008297:Male; D009020:Morphine / Q000494:pharmacology*; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D017473:Receptors, Opioid, kappa / Q000819:agonists / Q000502:physiology*; D012055:Reinforcement Schedule
D000700:Analgesics; D044482:Benzeneacetamides; D011759:Pyrrolidines; D017473:Receptors, Opioid, kappa; D009020:Morphine; C045444:U 69593