ketazocine and Substance-Withdrawal-Syndrome

Withdrawal contractures following brief exposure of guinea-pig ileum to enkephalin analogues, dynorphin A-(1-13) and beta-endorphin and the opiate drugs morphine, ketocyclazocine, buprenorphine and MR2034 were investigated. Following 2 min contact with the ileum a withdrawal contracture was induced by washout of (Met5)- and (Leu5)-enkephalin and by several enkephalin analogues but not by washout of (D-Ala2,D-Leu5)-enkephalinamide or any of the other drugs tested. Addition of naloxone precipitated withdrawal to all opioids tested except the kappa receptor preferential drugs ketocyclazocine and MR2034 and the mu receptor partial agonist, buprenorphine. The heights of the withdrawal contractures to enkephalin analogues were found to be dependent on the concentration of agonist and of naloxone, and on the duration of the contact period of opioid with the ileum. The naloxone-precipitated withdrawal responses to morphine, dynorphin A-(1-13) and the washout withdrawal response to (Met5)-enkephalin were inhibited by substance P antagonists thus supporting the previous proposal that substance P mediates the opiate withdrawal response. This study has shown that mu receptor agonists produced dependence in the guinea-pig ileum revealed by a withdrawal contracture on addition of naloxone, whereas dependence on kappa receptor agonists could not be revealed with naloxone. Since the guinea-pig ileum preparation has millimicron and kappa receptors it was concluded that the endogenous opioid peptides, enkephalins, beta-endorphin and dynorphin A-(1-13), all induced dependence by acting on mu receptors in this preparation.

Topics: Animals; Benzomorphans; Buprenorphine; Cyclazocine; Endorphins; Ethylketocyclazocine; Female; Guinea Pigs; Ileum; In Vitro Techniques; Male; Muscle, Smooth; Naloxone; Narcotics; Substance P; Substance Withdrawal Syndrome

Kainic acid is an analog of glutamate. The CA3-4 field of the hippocampus is extremely sensitive to its toxic properties. Intracerebroventricular injection of of nontoxic doses of kainic acid in rats produces behaviors similar to morphine withdrawal. Lesion of CA3-4 abolishes this response to kainic acid. Destruction of CA3-4 blocks the ability of Met-enkephalin, ketocyclazocine, and 5-hydroxytryptophan, but not sodium valproate or ice water to induce withdrawal-like behaviors. The actions of kainic acid, endorphins, and ketocyclazocine are blocked by naloxone and enhanced by opiate agonists. Sodium valproate, ice water, and withdrawal itself are released by naloxone and blocked by opiate agonists. Similar discriminations by CA3-4 lesions and challenge by naloxone and morphine may indicate that two neural circuits exist through which withdrawal-like behaviors are evoked. The hippocampal circuit is not directly involved in dependence, but may modulate withdrawal. Withdrawal-like behaviors are observed in rats in situations where behavior is blocked. These withdrawal-like behaviors are reminiscent of verbal reports of anxiety. In particular, wet-dog shakes in these situations may be analogous to shuddering. In humans, monosodium glutamate intolerance is associated with shuddering.

Topics: Animals; Cyclazocine; Endorphins; Enkephalin, Methionine; Enkephalins; Escape Reaction; Ethylketocyclazocine; Hippocampus; Humans; Injections, Intraventricular; Kainic Acid; Morphine Dependence; Pyrrolidines; Rats; Serotonin; Shivering; Substance Withdrawal Syndrome; Valproic Acid