Mechanistic Differences in Neuropathic Pain Modalities Revealed by Correlating Behavior with Global Expression Profiling

Abstract

SUMMARYChronic neuropathic pain is a major morbidity of neural injury, yet its mechanisms are incompletely understood. Hypersensitivity to previously non-noxious stimuli (allodynia) is a common symptom. Here, we demonstrate that the onset of cold hypersensitivity precedes tactile allodynia in a model of partial nerve injury, and this temporal divergence was associated with major differences in global gene expression in innervating dorsal root ganglia. Transcripts whose expression change correlates with the onset of cold allodynia were nociceptor related, whereas those correlating with tactile hypersensitivity were immune cell centric. Ablation of TrpV1 lineage nociceptors resulted in mice that did not acquire cold allodynia but developed normal tactile hypersensitivity, whereas depletion of macrophages or T cells reduced neuropathic tactile allodynia but not cold hypersensitivity. We conclude that neuropathic pain incorporates reactive processes of sensory neurons and immune cells, each leading to distinct forms of hypersensitivity, potentially allowing drug development targeted to each pain type.

Macrophage angiotensin II type 2 receptor triggers neuropathic pain

“…3C). Consistent with prior reports (40)(41)(42), increased microglia/MΦs were observed in the ipsilateral DRGs of SNI mice ( Fig. 3C).…”

Dorsal root ganglion macrophages contribute to both the initiation and persistence of neuropathic pain

“…Although several groups have implicated peripheral macrophages in nerve injury-induced pain initiation 5,21 , there is little consensus as to which macrophage population, in the DRG or at the nerve injury site, is most relevant. As selective depletion of DRG macrophages is difficult, here we instead targeted macrophages at the injury site, using an implanted cannula that delivered a lowdose of AP, one that killed macrophages at the injury site, but had no systemic effect, thus sparing the DRG.…”

“…To address this question, pharmacological and genetic approaches have been used to examine the behavioral consequence of depleting DRG macrophages in a nerve injury setting. For example, Cobos et al 5 reported that clodronate-mediated killing of DRG macrophages reduced the mechanical allodynia induced by nerve injury. However, other groups could not confirm those findings [6][7][8][9] , conceivably due to variability in the efficacy of clodronate 5,6 .…”

“…For example, Cobos et al 5 reported that clodronate-mediated killing of DRG macrophages reduced the mechanical allodynia induced by nerve injury. However, other groups could not confirm those findings [6][7][8][9] , conceivably due to variability in the efficacy of clodronate 5,6 . Other studies demonstrated clodronate killing of macrophages in injured peripheral nerves and concluded that these macrophages were critical to the neuropathic pain development 10,11 .…”

Silent cold-sensing neurons drive cold allodynia in neuropathic pain states

“…These findings are consistent with data which suggests TrkB-positive neurons are essential to tactile but not cold allodynia after nerve injury, indicating distinct modalities of allodynia are mechanistically different. 54,55 The majority of silent cold-sensing neurons expressed NaV1.8, a classic marker of nociceptors, in all three tested models. 33 This agrees with recent observations that NaV1.8, as well as labelling ~90% of C fibre nociceptors, is also expressed by ~40% of A fibre neurons, which also encompass nociceptors.…”