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Antinociception occurs with a reversal in alpha 2-adrenoceptor regulation of TNF production by peripheral monocytes/macrophages from pro- to anti-inflammatory.

Abstract
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.
AuthorsReeteka Sud, Robert N Spengler, Nader D Nader, Tracey A Ignatowski
JournalEuropean journal of pharmacology (Eur J Pharmacol) Vol. 588 Issue 2-3 Pg. 217-31 (Jul 07 2008) ISSN: 0014-2999 [Print] Netherlands
PMID18514187 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Analgesics
  • Lipopolysaccharides
  • Receptors, Adrenergic, alpha-2
  • Tumor Necrosis Factor-alpha
  • Amitriptyline
Topics
  • Amitriptyline (therapeutic use)
  • Analgesics (pharmacology)
  • Animals
  • Inflammation (metabolism)
  • Lipopolysaccharides (pharmacology)
  • Macrophages (metabolism)
  • Male
  • Monocytes (metabolism)
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Adrenergic, alpha-2 (physiology)
  • Sciatic Nerve (drug effects, pathology)
  • Tumor Necrosis Factor-alpha (analysis, biosynthesis)

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