Unravelling the problem of neuropathic pain

The detection of thermal, mechanical and other stimuli, and their interpretation as pain (that is, nociception), serves the useful adaptive purpose of guiding us through the world while accumulating a minimum of physical damage. But when the nerves that carry pain signals become damaged — for example, through diabetes, surgery or infection — maladaptive pain signals, termed neuropathic pain, can be generated from within the nervous system. This can, in the case of mechanical allodynia, turn normal activities involving touch into agonizing ordeals. Two papers recently published by Tsuda et al. in Nature and by Ibrahim et al. in the Proceedings of the National Academy of Science throw further light on the receptors involved in propagating neuropathic pain, and provide potential targets for therapeutic intervention.

Tsuda and colleagues used a rat model of allodynia to show that the P2X₄ receptor on spinal microglial cells, which has not previously been studied as a pain receptor, has a role in a form of neuropathic pain. The rat model involved cutting a peripheral sensory nerve, and then looking at the rats' response to tactile stimuli (that is, measuring mechanical allodynia); after a week, the rats in this study withdrew their paws from a light touch as if responding to a painful event.

P2X receptor (P2XR) antagonists were then infused into the spinal cords of the treated rats to see whether allodynia would be reduced. There are seven subtypes of P2XR ion channels: subtypes P2X₃ and P2X₂ are found in high numbers on specific nociceptive neurons, thereby providing the rationale for studying P2XR antagonists. Surprisingly, Tsuda et al. found that PPADS, an antagonist of P2XRs on nociceptive neurons but not of P2X₄ and some other subtypes, did not reduce allodynia, whereas TNP-ATP, which blocks all P2XR subtypes, did. So Tsuda and colleagues determined which receptor was being blocked, and its location. Fluorescently labelled antibodies to P2X₄ localized to microglia on the side of the spine where the nerve was cut; this, combined with the inhibition data and knowledge that microglia only express the receptors P2X₇ (which is inhibited by PPADS) and P2X₄, led to the identification of P2X₄ as the key receptor. Furthermore, an antisense oligonucleotide against P2X₄ infused into rats' spinal cords after nerve damage reduced the severity of allodynia. These results identify a new receptor in the pain process, and provide strong evidence of the functional role of microglia.

Ibrahim et al. also explored neuropathic pain, and set out to address the hypothesis that activation of the CB₂ cannabinoid receptor would reduce pain hypersensitivity by using AM1241, a CB₂-receptor-selective agonist. AM1241 was found to dose-dependently reverse tactile and thermal hypersensitivity produced by cutting the L5 and L6 spinal nerves in rats. In addition, these effects were ablated by an antagonist selective for CB₂ receptors, but not by a CB₁-receptor-specific antagonist. Furthermore, AM1241 reversed allodynia in mice lacking CB₁ receptors, establishing that CB₂ is the crucial receptor.

Some of the current treatment options for neuropathic pain have unwanted side effects on the central nervous system (CNS), and so drugs directed against targets not found in the CNS would make attractive agents. CB₂ receptors, which are not expressed in the brain or CNS, fit the bill.