Distinct neurochemical features of acute and persistent pain

Abstract

To address the neurochemistry of the mechanisms that underlie the development of acute and persistent pain, our laboratory has been studying mice with deletions of gene products that have been implicated in nociceptive processing. We have recently raised mice with a deletion of the preprotachykinin-A gene, which encodes the peptides substance P (SP) and neurokinin A (NKA). These studies have identified a specific behavioral phenotype in which the animals do not detect a window of "pain" intensities; this window cuts across thermal, mechanical, and chemical modalities. The lowered thermal and mechanical withdrawal thresholds that are produced by tissue or nerve injury, however, were still present in the mutant mice. Thus, the behavioral manifestations of threshold changes in nociceptive processing in the setting of injury do not appear to require SP or NKA. To identify relevant neurochemical factors downstream of the primary afferent, we are also studying the dorsal horn second messenger systems that underlie the development of tissue and nerve injury-induced persistent pain states. We have recently implicated the gamma isoform of protein kinase C (PKCgamma) in the development of nerve injury-induced neuropathic pain. Acute pain processing, by contrast, is intact in the PKCgamma-null mice. Taken together, these studies emphasize that there is a distinct neurochemistry of acute and persistent pain. Persistent pain should be considered a disease state of the nervous system, not merely a prolonged acute pain symptom of some other disease conditions.

Figure 1

(Left) Micrograph from the lumbar spinal cord of the rat. It illustrates the restricted distribution of PKCγ immunoreactivity to interneurons in the inner part of lamina II of the superficial dorsal horn. (Right) Distribution of Fos-immunoreactive neurons in the L4 cord dorsal horn evoked by an injection of formalin into the ipsilateral hindpaw. The rat was killed 1 hr after the formalin injection. Note that there are many labeled neurons in the most superficial laminae (I and outer II), but that there is a distinct band (corresponding to the inner part of lamina II; arrows) in which there is very little Fos expression. Thus although the small-diameter afferents that innervate lamina II are chemonociceptors, their activation appears not to induce Fos in the neurons that they target. (×60.)