Desensitization to substance P following intrathecal injection. A technique for investigating the role of substance P in nociception.

The intrathecal injection of substance P (SP) (2.5-15 micrograms) has been shown to produce hyperalgesia in the rat tail flick test. Repeated injection of SP (7.5 or 15 micrograms) or pretreatment with two of these doses produces desensitization to this hyperalgesic response. Desensitization is dose-related with respect to degree and duration. This phenomenon is relatively specific because the hyperalgesic response to methysergide, a serotonin receptor antagonist, is unaffected, while that produced by phentolamine, an adrenergic receptor antagonist, is much less affected than that of SP. Pretreatment with a desensitizing regimen of SP potentiates the antinociceptive effect of morphine and baclofen when they are tested immediately after the regimen but if a 30 min delay is permitted, an inhibition of their effects is observed. These results support the notion that the spinal antinociceptive effect of morphine and baclofen is due to an interaction with SP mechanisms in the spinal cord, the nature of which may be more complex than is presently understood. Desensitization produces no change in baseline responsiveness in the tail flick test. This suggests that the hyperalgesic response to SP is due either to an action at a site other than the primary afferent synapse, or if it is at this site either compensatory mechanisms occur or SP is not the primary determinant of tail flick latency but may play a modulatory role.