Substance P markedly potentiates the antinociceptive effects of morphine sulfate administered at the spinal level.

Abstract

The undecapeptide substance P and the alkaloid morphine sulfate are two agents previously thought to have opposite roles in the mediation of spinal nociceptive processes. The present report, however, demonstrates that low doses of substance P when coadministered with marginally effective doses of morphine sulfate into the rat subarachnoid space produce 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 analgesic response is mediated by opioid-responsive neurons. In addition, the putative immediate precursor form of substance P (i.e., substance P-glycine) may substitute for the mature compound in the potentiated pharmacological effect. Moreover, the described synergism is unaffected by transection of the spinal cord, demonstrating the lack of supraspinal modulation of the observed phenomenon. Based on these observations, we are now able to dissociate opioid-potentiating and analgesic properties of substance P from traditional hyperalgesic effects realized at significantly higher concentrations. Consistent with previous biochemical data, a likely mechanism underlying the peptide-mediated enhancement of opioid analgesia may center on the ability of substance P to release endogenous opioid peptides within the local spinal cord environment. Finally, the pharmacological relationship of coadministered substance P and morphine sulfate established here supports the hypothesis that spinal tachykinin and opioid systems have a direct functional interaction in the modulation of local nociceptive responses.

A substance P-opioid chimeric peptide as a unique nontolerance-forming analgesic

“…ESP7 administered in the presence of 250 pmol of RP67580 over the course of 4 days behaved as a typical MOR-preferring opioid analgesic. The peptide displayed a T 1/2 of approximately 1 day for the decay of opioid efficacy as a function of time, similar to that observed for MS administered in the absence of SP or MS administered in the presence of SP and RP67580 (15). RP67580 alone produced no analgesic effects.…”

“…Results from previous experiments in our laboratory directly emphasize a pivotal role for SP in opioid analgesia (15). Low concentrations of SP, when coadministered with marginally effective doses of MS into the rat subarachnoid space, produce a markedly enhanced analgesic response as monitored by the tailflick test.…”

“…In light of the established literature indicating that SP-and opioid-expressing neurons presumably mediate opposite physiological effects at the spinal level, investigators have tended to overlook the role of SP and SP receptors (SPRs) in the regulation of endogenous opioid systems (10)(11)(12)(13)(14), particularly in the area of analgesic responsiveness. Previous pharmacological data from our group strongly suggest that SP released in the dorsal horn plays an important role in antinociception by regulating analgesic activity of the postsynaptic opioid systems (15,16). In particular, we demonstrated that low doses of SP, when coadministered with marginally effective doses of morphine sulfate (MS) into the rat subarachnoid space, produce a markedly enhanced analgesic response.…”

“…4). RP67580 (250 pmol) (K i ϭ 4 nM) was previously shown to selectively antagonize the SPR, with minimal activity at the NK-2 or NK-3 receptors (15). ESP7 administered in the presence of 250 pmol of RP67580 over the course of 4 days behaved as a typical MOR-preferring opioid analgesic.…”

Role of opioid receptors in the spinal antinociceptive effects of neuropeptide FF analogues

“…The prolonged enhancement of ,u-and 6-opioid antinociceptive action by agents previously thought to have opposite roles in the mediation of nociceptive processes is reminescent of the potentiation of morphine analgesia in the spinal cord by 10 to 100 pmol substance P (without any effect on tail-flick thresholds alone) (Kream et al, 1993). Another interesting finding in our study is the sharp contrast between brain and spinal cord for NPFF/opioid interaction.…”