ketazocine and Morphine-Dependence

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

Three different syndromes produced by congeners of morphine have been identified in the nondependent chronic spinal dog. These syndromes have been attributed to interaction of agonists with three distinguishable receptors (mu, kappa and sigma). Morphine is the prototype agonist for the mu receptor, ketocyclazocine for the kappa receptor and SKF-10,047 for the sigma receptor. The morphine syndrome (mu) in the dog is characterized by miosis, bradycardia, hypothermia, a general depression of the nociceptive responses and indifference to environmental stimuli. Ketocyclazocine (kappa) constricts pupils, depresses the flexor reflex and produces sedation but does not markedly alter pulse rate or the skin twitch reflex. SKF-10,047 (sigma), in contrast to morphine and ketocyclazocine, causes mydriasis, tachypnea, tachycardia and mania. The effects of these three drugs can be antagonized by the pure antagonist naltrexone, indicating that they are agonists. Further, chronic administration of morphine, ketocyclazocine and SKF-10,047 induces tolerance to their agonistic effects. Morphine suppresses abstinence in morphine-dependent dogs while ketocyclazocine does not. Ketocyclazocine at best precipitated only a liminal abstinence syndrome in the morphine-dependent dog, indicating that it had little affinity for the morphine receptor. Ketocyclazocine thus appears to be a selective agonist at the kappa receptor. Further, it has been shown that buprenorphine is a partial agonist of the mu type which both suppressed and precipitated abstinence in the morphine-dependent dog while morphine and propoxyphene are stronger agonists. Apomorphine and SKF-10,047 produce similar pharmacologic effects suggesting that sigma activity may involve a dopaminergic mechanism.

Topics: Animals; Apomorphine; Cyclazocine; Cyclopropanes; Dextropropoxyphene; Dogs; Ethylketocyclazocine; Humans; Morphinans; Morphine; Morphine Dependence; Nalorphine; Naltrexone; Phenazocine; Spinal Cord