Minocycline attenuates mechanical allodynia and proinflammatory cytokine expression in rat models of pain facilitation.
Activated glial cells (microglia and astroglia) in the spinal cord play a major role in mediating enhanced pain states by releasing proinflammatory cytokines and other substances thought to facilitate pain transmission. In the present study, we report that intrathecal administration of minocycline, a selective inhibitor of microglial cell activation, inhibits low threshold mechanical allodynia, as measured by the von Frey test, in two models of pain facilitation. In a rat model of neuropathic pain induced by sciatic nerve inflammation (sciatic inflammatory neuropathy, SIN), minocycline delayed the induction of allodynia in both acute and persistent paradigms. Moreover, minocycline was able to attenuate established SIN-induced allodynia 1 day, but not 1 week later, suggesting a limited role of microglial activation in more perseverative pain states. Our data are consistent with a crucial role for microglial cells in initiating, rather than maintaining, enhanced pain responses. In a model of spinal immune activation by intrathecal HIV-1 gp120, we show that the anti-allodynic effects of minocycline are associated with decreased microglial activation, attenuated mRNA expression of interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), IL-1beta-converting enzyme, TNF-alpha-converting enzyme, IL-1 receptor antagonist and IL-10 in lumbar dorsal spinal cord, and reduced IL-1beta and TNF-alpha levels in the CSF. In contrast, no significant effects of minocycline were observed on gp120-induced IL-6 and cyclooxygenase-2 expression in spinal cord or CSF IL-6 levels. Taken together these data highlight the importance of microglial activation in the development of exaggerated pain states.
Ledeboer
Annemarie
A
Department of Psychology and the Center for Neuroscience, University of Colorado at Boulder, Campus Box 345, Boulder, CO 80309-0345, USA.
Sloane
Evan M
EM
Milligan
Erin D
ED
Frank
Matthew G
MG
Mahony
John H
JH
Maier
Steven F
SF
Watkins
Linda R
LR
D000818:Animals; D016207:Cytokines / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006941:Hyperesthesia / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism*; D007278:Injections, Spinal; D008297:Male; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D008911:Minocycline / Q000008:administration & dosage*; D018696:Neuroprotective Agents / Q000008:administration & dosage; D010523:Peripheral Nervous System Diseases / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism*
D016207:Cytokines; D018696:Neuroprotective Agents; D008911:Minocycline