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The Journal of Neuroscience, September 28, 2005, 25(39):8988-8994; doi:10.1523/JNEUROSCI.2995-05.2005

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Behavioral/Systems/Cognitive
2-Adrenoceptor Stimulation Transforms Immune Responses in Neuritis and Blocks Neuritis-Induced Pain

E. Alfonso Romero-Sandoval,¹ Charles McCall,² and James C. Eisenach¹

¹Department of Anesthesiology and Center for the Study of Pharmacologic Plasticity in the Presence of Pain, and ²Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157-1009

Neuropathic pain may be primarily driven by immune responses in peripheral nerves. Peripherally released catecholamines may exacerbate neuropathic pain and also modulate immune responses in a complex and sometimes opposing manner by actions on multiple adrenoceptor subtypes. We showed previously that injection of the 2-adrenoceptor agonist clonidine at the site of peripheral nerve injury reduces pain behavior and local tissue pro-inflammatory cytokine content in rats. The current study used a model of acute inflammatory neuritis to test the efficacy and mechanisms of action of2-adrenoceptor stimulation to reduce pain. Zymosan, injected on the sciatic nerve, caused hypersensitivity to mechanical stimuli ipsilateral to injection and contralaterally, so-called mirror image pain. Ipsilateral hypersensitivity was inhibited dose-dependently by perineural injection of clonidine. Zymosan increased leukocyte number at the site of injection 3 d later as well as their content of interleukin 1 (IL-1), IL-1, and IL-6. Perineural clonidine prevented both the increase in leukocyte number and cytokine expression induced by zymosan. Additionally, clonidine reduced the capacity of leukocytes to express pro-inflammatory cytokines as assessed by treatment of cells ex vivo with lipopolysaccharide, whereas no repression of IL-10 production occurred. Clonidine reduced the number of macrophages and lymphocytes as well as their expression of tumor necrosis factor . All of the effects of clonidine were prevented by coadministration of an2A-adrenoceptor-preferring antagonist. These results suggest that 2-adrenoceptor stimulation transforms cytokine gene expression, especially in macrophages and lymphocytes from a pro- to an anti-inflammatory profile in the setting of neuritis, likely relieving neuritis-induced pain by this mechanism.

Key words: clonidine; neuritis; cytokines; 2-adrenoceptors; neuropathic pain; inflammation

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Received July 20, 2005; revised August 17, 2005; accepted August 23, 2005.

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				F. A. White, H. Jung, and R. J. Miller Chemokines and the pathophysiology of neuropathic pain PNAS, December 18, 2007; 104(51): 20151 - 20158. [Abstract] [Full Text] [PDF]

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