Tumor necrosis factor-alpha (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 alpha 2-adrenoceptor inhibition of
norepinephrine release. alpha 2-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 alpha 2-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 alpha 2-adrenoceptor in vitro. alpha 2-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 alpha 2-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 alpha 2-adrenoceptor regulation of TNF production from pro- to anti-inflammatory is associated with effective alleviation of
thermal hyperalgesia. Thus, alpha 2-adrenoceptor regulation of peripheral TNF production may serve as a potential
biomarker to evaluate therapeutic regimens.