Antinociception occurs with a reversal in α2-adrenoceptor regulation of TNF production by peripheral monocytes/macrophages from pro- to anti-inflammatory

Tumor necrosis factor-α (TNF) plays a role in neuropathic pain. During neuropathic pain development in the chronic constriction injury model, elevated TNF levels in the brain occur in association with enhanced α2-adrenoceptor inhibition of norepinephrine release. α2-Adrenoceptors are also located on peripheral macrophage where they normally function as pro-inflammatory, since they increase the production of the cytokine TNF, a proximal mediator of inflammation. How the central increase in TNF affects peripheral α2-adrenoceptor function was investigated. Male, Sprague–Dawley rats had four loose ligatures placed around the right sciatic nerve. Thermal hyperalgesia was determined by comparing hind paw withdrawal latencies between chronic constriction injury and sham-operated rats. Chronic constriction injury increased TNF immunoreactivity at the lesion and the hippocampus. Amitriptyline, an antidepressant that is used as an analgesic, was intraperitoneally administered (10 mg/kg) starting simultaneous with ligature placement (day-0) or at days-4 or -6 post-surgery. Amitriptyline treatment initiated at day-0 or day-4 post-ligature placement alleviated hyperalgesia. When initiated at day-0, amitriptyline prevented increased TNF immunoreactivity in the hippocampus and at the lesion. A peripheral inflammatory response, macrophage production of TNF, was also assessed in the current study. Lipopolysaccharide (LPS)-stimulated production of TNF by whole blood cells and peritoneal macrophages was determined following activation of the α2-adrenoceptor in vitro. α2-Adrenoceptor regulation of TNF production from peripheral immune-effector cells reversed from potentiation in controls to inhibition in chronic constriction injured rats. This effect is accelerated with amitriptyline treatment initiated at day-0 or day-4 post-ligature placement. Amitriptyline treatment initiated day-6 post-ligature placement did not alleviate hyperalgesia and prevented the switch from potentiation to inhibition in α2-adrenoceptor regulation of TNF production. Recombinant rat TNF i.c.v. microinfusion reproduces the response of peripheral macrophages from rats with chronic constriction injury. A reversal in peripheral α2-adrenoceptor regulation of TNF production from pro- to anti-inflammatory is associated with effective alleviation of thermal hyperalgesia. Thus, α2-adrenoceptor regulation of peripheral TNF production may serve as a potential biomarker to evaluate therapeutic regimens.