Perineural clonidine reduces p38 mitogen-activated protein kinase activation in sensory neurons.

Perineural injection of clonidine at the site of nerve injury reduces hypersensitivity while simultaneously reducing leukocyte number and cytokine expression and hyperexcitability in sensory neurons. The activation of p38 mitogen-activated protein kinase in sensory neurons contributes to the development and maintenance of inflammatory and neuropathic pain. Here, we tested whether perineural clonidine affected activation of p38 mitogen-activated protein kinase following partial sciatic nerve ligation. Perineural clonidine significantly increased withdrawal threshold and concomitantly reduced phosphorylation of p38 mitogen-activated protein kinase in sensory neurons ipsilateral to injury. Clonidine's effects were blocked by the alpha2-adrenoceptor antagonist, BRL44408. These data suggest that activation of alpha2-adrenoceptors at the site of nerve injury, probably by immune modulation, reduces intracellular signaling in primary afferents that leads to hypersensitivity.