Perioperative administration of the alpha2-adrenoceptor agonist clonidine at the site of nerve injury reduces the development of mechanical hypersensitivity and modulates local cytokine expression.
The development of chronic pain after surgery is not rare. Nerve injury from complete or partial nerve section during surgery leads to macrophage recruitment and release of pro-inflammatory cytokines, leading in turn to sensitization. Macrophages also express alpha2-adrenoceptors, and we previously demonstrated a prolonged reduction in hypersensitivity following peri-neural injection of the alpha2-adrenoceptor agonist, clonidine, in rats with chronic nerve injury. The current study tested whether peri-neural clonidine at the time of injury could also prevent development of hypersensitivity. Rats underwent partial ligation of one sciatic nerve, and peri-neural saline, clonidine or a combination of clonidine and the alpha2A-adrenceptor-preferring antagonist, BRL44408, were administered before wound closure and, in some animals, also 24 and 48 h later. The single clonidine injection reduced hypersensitivity for only 5 h, whereas repeated injection for three days reduced hypersensitivity for 28 days. Peri-neural clonidine reduced the increase in tissue content of the proinflammatory cytokines IL-1beta and particularly TNFalpha in sciatic nerve, DRG and spinal cord while increasing concentrations of the anti-inflammatory cytokine TGF-beta1. Clonidine's effects on behavior and TNFalpha content were blocked by BRL44408. We conclude that peri-neural administration of clonidine at the site and time of injury reduces the degree of hypersensitivity in part by altering the balance of pro- and anti-inflammatory cytokines through activation of alpha2A-adrenoceptors. These results support testing of whether clonidine, as an adjuvant in continuous peripheral nerve blocks in settings of known major nerve injury, such as limb amputation, might prevent the development of chronic pain.
D000316:Adrenergic alpha-Agonists / Q000008:administration & dosage*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003000:Clonidine / Q000008:administration & dosage*; D016207:Cytokines / Q000378:metabolism*; D004338:Drug Combinations; D006930:Hyperalgesia / Q000517:prevention & control*; D007093:Imidazoles / Q000008:administration & dosage; D007211:Indoles / Q000008:administration & dosage; D007375:Interleukin-1 / Q000378:metabolism; D007430:Intraoperative Care; D054833:Isoindoles; D008026:Ligation; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D017288:Pain Threshold / Q000187:drug effects; D010812:Physical Stimulation; D011182:Postoperative Care; D011300:Preoperative Care; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D012584:Sciatic Nerve / Q000293:injuries* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014947:Wounds and Injuries / Q000150:complications / Q000378:metabolism / Q000523:psychology
D000316:Adrenergic alpha-Agonists; D016207:Cytokines; D004338:Drug Combinations; D007093:Imidazoles; D007211:Indoles; D007375:Interleukin-1; D054833:Isoindoles; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D003000:Clonidine; C072125:BRL 44408