Antinociception occurs with a reversal in alpha 2-adrenoceptor regulation of TNF production by peripheral monocytes/macrophages from pro- to anti-inflammatory.
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.
Sud
Reeteka
R
Department of Pathology and Anatomical Sciences, School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York, Buffalo, NY 14214, USA.
Spengler
Robert N
RN
Nader
Nader D
ND
Ignatowski
Tracey A
TA
D000639:Amitriptyline / Q000627:therapeutic use; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D007249:Inflammation / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D009000:Monocytes / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018341:Receptors, Adrenergic, alpha-2 / Q000502:physiology*; D012584:Sciatic Nerve / Q000187:drug effects / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000096:biosynthesis*
D000700:Analgesics; D008070:Lipopolysaccharides; D018341:Receptors, Adrenergic, alpha-2; D014409:Tumor Necrosis Factor-alpha; D000639:Amitriptyline