SUBSTANCE-P MARKEDLY POTENTIATES THE ANTINOCICEPTIVE EFFECTS OF MORPHINE-SULFATE ADMINISTERED AT THE SPINAL LEVEL

The undecapeptide substance P and the alkaloid morphine sulfate are tw o agents previously thought to have opposite roles in the mediation of spinal nociceptive processes. The present report, however, demonstrat es that low doses of substance P when coadministered with marginally e ffective doses of morphine sulfate into the rat subarachnoid space pro duce a markedly enhanced analgesic response, as monitored by the tail- flick test. This pharmacological effect is blocked by prior treatment with the opioid antagonist naloxone, indicating that the potentiated a nalgesic response is mediated by opioid-responsive neurons. In additio n, the putative immediate precursor form of substance P (i.e., substan ce P-glycine) may substitute for the mature compound in the potentiate d pharmacological effect. Moreover, the described synergism is unaffec ted by transection of the spinal cord, demonstrating the lack of supra spinal modulation of the observed phenomenon. Based on these observati ons, we are now able to dissociate opioid-potentiating and analgesic p roperties of substance P from traditional hyperalgesic effects realize d at significantly higher concentrations. Consistent with previous bio chemical data, a likely mechanism underlying the peptide-mediated enha ncement of opioid analgesia may center on the ability of substance P t o release endogenous opioid peptides within the local spinal cord envi ronment. Finally, the pharmacological relationship of coadministered s ubstance P and morphine sulfate established here supports the hypothes is that spinal tachykinin and opioid systems have a direct functional interaction in the modulation of local nociceptive responses.