Perineural Clonidine Reduces Mechanical Hypersensitivity and Cytokine Production in Established Nerve Injury

Abstract

Partial sciatic nerve ligation (PSNL) produces axonal damage, a local inflammatory response, and wallerian degeneration. Cytokines secreted near the site of nerve injury are thought to play important roles in development and maintenance of central sensitization and neuropathic pain. Injection of clonidine at the site and time of nerve injury slows the development of PSNL-induced hypersensitivity and reduces local cytokine expression by actions on alpha2 adrenoceptors. The current study tested whether clonidine would have a similar effect in established nerve injury. Rats underwent unilateral PSNL, and perineural saline, clonidine, or BRL44408 plus clonidine was injected 2 weeks later. Three days after perineural injection, withdrawal threshold to mechanical stimulation of the hind paw ipsilateral and contralateral to PSNL was determined, and tissues were removed for cytokine analysis. PSNL was accompanied by a proinflammatory pattern of cytokine content in neural structures and hypersensitivity ipsilaterally with few changes contralaterally. Perineural clonidine, but not saline, partially reversed the hypersensitivity, accompanied by reduced concentrations of interleukin 6 and interleukin 1beta in the sciatic nerve. The effect of clonidine on hypersensitivity and these cytokines was blocked by the alpha2-adrenoceptor antagonist, BRL44408. These data suggest that perineural clonidine acts on alpha2 adrenoceptors to reduce hypersensitivity in established nerve injury, likely by an immunomodulatory mechanism, and may be effective in patients in the weeks after nerve injury.