Neurobehavioral evidence for kappa agonist activity of the morphinan derivative 14-beta-methyl 8-oxacyclorphan [BC (3016)].
The purpose of the present study was to determine if the in vivo neurobehavioral effects of the morphinan 14-beta-methyl 8-oxacyclorphan, [BC (3016)], would reflect the kappa agonist activity found in our previous in vitro studies. The effects of intracisternal administration of various doses (10-80 micrograms) of BC (3016) on body temperature, muscle rigidity, nociception of thermal, chemical and mechanical stimuli as well as its ability to induce catalepsy were examined. The effects of intrathecal administration of the same doses of the compound on reactivity of animals to a thermal stimulus were also assessed. Finally, the ability of BC (3016) to antagonize well known neurobehavioral effects of morphine was investigated. Results indicate that the analgesic properties of BC (3016) resemble those of typical kappa agonists: Intracisternal administration of the drug failed to affect nociception to an aversive thermal stimulus but markedly reduced the reactivity of animals subjected to noxious chemical or mechanical stimuli. On the other hand, intrathecal administration of BC (3016) significantly attenuated nociception of animals to a thermal stimulus. The in vivo neurobehavioral effects of BC (3016) appear to be kappa selective since the drug did not decrease body temperature, increase muscular tone or induce catalepsy, three effects generally attributed to mu agonists. Furthermore, BC (3016) antagonized the immobility, trunk rigidity, catalepsy and analgesia induced by morphine. In summary, the present results reveal that BC (3016) displays a profile of neurobehavioral effects similar to that of well known kappa agonists.
Jolicoeur
F B
FB
Department of Psychiatry, Faculty of Medicine, Sherbrooke University, Quebec, Canada.
Menard
D
D
Rivest
R
R
Lemaire
S
S
Belleau
B
B
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001831:Body Temperature / Q000187:drug effects; D002375:Catalepsy / Q000139:chemically induced; D002946:Cisterna Magna; D006358:Hot Temperature; D007267:Injections; D007278:Injections, Spinal; D008297:Male; D009019:Morphinans / Q000031:analogs & derivatives* / Q000494:pharmacology; D009129:Muscle Tonus / Q000187:drug effects; D009270:Naloxone / Q000494:pharmacology; D009619:Nociceptors / Q000187:drug effects; D051381:Rats; D011957:Receptors, Opioid / Q000502:physiology*; D017473:Receptors, Opioid, kappa
D009019:Morphinans; D011957:Receptors, Opioid; D017473:Receptors, Opioid, kappa; D009270:Naloxone; C050133:14-methyl-8-oxacyclorphan