Spinal opioid analgesia: How critical is the regulation of substance P signaling?

Although opioids can reduce stimulus-evoked efflux of Substance P (SP) from nociceptive primary afferents, the consequences of this reduction on spina l cord nociceptive processing has not been studied. Rather than assaying SP release, in the present study we examined the effect of opioids on two pos tsynaptic measures of SP release, Fos expression and neurokinin-1 (NK-1) re ceptor internalization, in the rat. The functional significance of the latt er was first established in in vitro studies that showed that SP-induced Ca 2+ mobilization is highly correlated with the magnitude of SP-induced NK-1 receptor internalization in dorsal horn neurons. Using an in vivo analysis, we found that morphine had little effect on noxious stimulus-evoked intern alization of the NK-1 receptor in lamina I neurons. However, internalizatio n was reduced when we coadministered morphine with a dose of an NK-1 recept or antagonist that by itself was without effect. Thus, although opioids may modulate SP release, the residual release is sufficient to exert maximal e ffects on the target NK-1 receptors. Morphine significantly reduced noxious stimulus-induced Fos expression in lamina I, but the Fos inhibition was le ss pronounced in neurons that expressed the NK-1 receptor. Taken together, these results suggest that opioid analgesia predominantly involves postsyna ptic inhibitory mechanisms and/or presynaptic control of non-SP-containing primary afferent nociceptors.