EFFECTS OF MORPHINE-LIKE AND NALORPHINE-LIKE DRUGS IN NONDEPENDENT, MORPHINE-DEPENDENT AND CYCLAZOCINE-DEPENDENT CHRONIC SPINAL DOG

Abstract

A series of morphine-like and nalorphine-like drugs were studied in the nondependent, morphine-dependent and cyclazocine-dependent chronic spinal dog. In the nondependent dog, 3 profiles of activity were found which could be utilized to distinguish between morphine, WIN 35,197-2 [(+)-3-(cyclopropylmethyl)-5-(eq)-ethyl-2''-hydroxy-8-keto-9-(ax)-methyl-6,7-benzomorphan methane sulfonate] and cyclazocine. Propiram, a prototypic partial agonist of the morphine type, produced morphine-like effects in nondependent dogs and both precipitated and suppressed abstinence in morphine-dependent dogs. WIN 35,197-2, a strong agonist in the guinea pig ileum which has been shown to be resistant to antagonism by naloxone, neither precipitated nor suppressed morphine abstinence but suppressed cyclazocine abstinence. In the nondependent dog, it depressed the flexor reflex but not skin twitch reflex. Cyclazocine altered reflex activity much like WIN 35,197-2 but produced tachycardia, tachypnea, mydriasis and canine delirium. The morphine and cyclazocine precipitated and withdrawal abstinence syndromes were qualitatively different. Twenty times as much naltrexone was needed to precipitate abstinence in cyclazocine-dependent dogs as was needed to precipitate abstinence in morphine-dependent dogs. Nalorphine both precipitated and suppressed cyclazocine abstinence and appeared to be a partial agonist of the nalorphine-type. Morphine suppressed the cyclazocine abstinence syndrome. Cross-tolerance was not observed in ketocyclazocine-dependent dogs. These data were consistent with the hypothesis that there were strong and partial agonists of the .mu. and .kappa. types, and further, that physical dependence on morphine and cyclazocine was mediated through different receptors. WIN 35,197-2 appeared to be a pure strong agonist of the .kappa. type. Cyclazocine was a .mu. antagonist and mixed .kappa. and .sigma. agonist.