228) Pain Hypersensitivity in Chronic Traumatic Neuropathy is Mediated by Peripheral Macrophages and AT2R Signaling

Traumatic modes of experimental neuropathy in rodents have been extensively utilized in pre-clinical studies to understand mechanisms underlying chronic neuropathic pain, and to test the in vivo efficacy of experimental and known analgesic drugs. The vast majority of studies probe anatomical, transcriptomic and tissue/cell functional analysis, as well as pain hypersensitivity-related behavioral outcome measures within 1 to 3 weeks of the induction of trauma/surgical procedures. This models the acute/sub-chronic phases of neuropathic pain in humans, and thus represents a disconnect from chronic neuropathy conditions/diseases and the associated pain in humans. With this in mind, we investigated whether the mechanisms elucidated at 1 to 3 weeks post-injury also drive pain hypersensitivity at more chronic stages (>100 days post-injury). We used evoked and voluntary behavioral measures of mechanical and cold hypersensitivity along with immunohisochemical analysis in the spared nerve injury (SNI) model of traumatic neuropathy in mice. Elevated macrophage density was detectable in the injured nerve at this late stage, and mechanical and cold hypersensitivity also persist in these animals. We recently reported a role for peripheral macrophages and the function of the type II angiotensin II receptor (known as AT2R) therein, at the site of nerve injury in the development of neuropathic pain. In the present study, we found that the AT2R antagonist EMA401, which is currently in phase II clinical trials for post-herpetic neuralgia and diabetic neuropathic pain, attenuated mechanical and cold pain hypersensitivity in SNI mice. Collectively, our observations suggest that in addition to being a crucial driver of neuropathic pain hypersensitivity in the more acute stages, peripheral macrophage infiltration and AT2R signaling therein continues to drive sustained pain hypersensitivity associated with neuropathy in chronic pathological states of the disease.