The involvement of substance P and neurokinin-1 receptors in the responses of rat dorsal horn neurons to noxious but not to innocuous mechanical stimuli applied to the knee joint.

In 29 anesthetized rats, the involvement of substance P and neurokinin-1 receptors in the spinal processing of mechanosensory innocuous and noxious information from the knee and ankle joint was investigated. In 21 rats, multibarrel electrodes were used to record from 46 spinal cord neurons with afferent input from the knee joint and to administer agonists and antagonists by microinophoresis. In 35 of 46 nociceptive neurons, substance P (ejected at 20-120 nA) caused an excitation and/or an increase in responses to innocuous and noxious pressure applied to the knee and ankle. These effects were reduced by ionophoretic application of the specific neurokinin-1 receptor antagonist CP96,345 (ejected at 25-80 nA) but not by CP96,344, its inactive enantiomer. CP96,345 dose-dependently reduced the responses to noxious pressure applied to the knee joint in 28/28 substance P-sensitive neurons but not those to innocuous pressure in 23/23 substance P-sensitive wide dynamic range neurons. CP96,345 did not affect responses to pressure in substance P-insensitive neurons and the inactive enantiomer CP96,344 had no effect in any of the neurons tested. Using microprobes coated with antibody to substance P, intraspinal release of immunoreactive substance P was found to be evoked by noxious pressure applied to the knee but not by innocuous pressure in 8 rats. Both sets of data suggest a role for substance P and neurokinin-1 receptors in the neuronal mechanisms in the spinal cord related to nociception and pain in the normal joint.