Involvement of biogenic amines with the mechanisms of novel analgesics.

The analgesic activity of the kappa opioid agonist, U-50,488H, was markedly antagonized by pretreatment with reserpine, p-chlorophenylalanine, and ketanserin. Likewise, analgesic doses of U-50,488H enhance serotonin metabolism. These results suggest that kappa analgesia requires serotonin acting through 5-HT2 receptors. The non-opioid analgesic, nefopam HCl, though a blocker of biogenic amine uptake, displays an analgesic spectrum of action more similar to that of amphetamine than that of the tricyclic antidepressants or serotonin uptake blockers. Likewise p-chlorophenylalanine and ketanserin do not block nefopam analgesia nor do naloxone, atropine, yohimbine, propranolol or haloperidol. However, as reserpine does block nefopam analgesia, biogenic amines acting at other receptors may be involved. The observation that m-tyrosine causes behavioral effects similar to high doses of nefopam suggested that they might be acting through similar mechanisms. However, although m-tyrosine causes analgesia, it is blocked by yohimbine. This suggests that alpha2-adrenoreceptors are involved in m-tyrosine analgesia and that it differs in mechanism from nefopam analgesia.