• L R Watkins, D Martin, P Ulrich, K J Tracey, and S F Maier.
• Department of Psychology, University of Colorado at Boulder, 80309, USA. lwatkins@clipr.colorado.edu
• Pain. 1997 Jul 1; 71 (3): 225-35.

AbstractSubcutaneous (s.c.) injection of formalin induces a rapid and prolonged hyperalgesia across widespread areas of the body. This hyperalgesic state involves a brain-to-spinal cord pathway, likely arising from the nucleus raphe magnus. The present study examined whether subsequent activation of spinal cord glia may be critical for the hyperalgesic state to be observed in rats. Glia were considered candidates as they can, upon activation, release a variety of substances known to be critical for the mediation of subcutaneous formalin-induced hyperalgesia including glutamate, aspartate, nitric oxide, arachidonic acid and cyclooxygenase products such as prostaglandins. This series of experiments demonstrate that formalin-induced hyperalgesia in rats can be blocked by intrathecal administration of agents that: (a) disrupt glial function (using either 1 nmol fluorocitrate which is a glial metabolic inhibitor, or 9 microg CNI-1493 which disrupts synthesis of nitric oxide and cytokines in monocyte-derived cells; ANOVA revealed reliable group effects for each drug with P < 0.0005); or (b) disrupt the action of glial products (using 10, 50, or 100 microg of a human recombinant interleukin-1 receptor antagonist or 10 microl antibody directed against nerve growth factor; ANOVA revealed reliable group effects for each drug with P < 0.001). Disruption appeared to be selective, as blockade of only select glial products was effective. That is, up to 120 microg of a functional antagonist of tumor necrosis factor-alpha (TNF binding protein) and 5 microl of an antibody against complement-3 produced no statistically reliable reduction in formalin-induced hyperalgesia. Taken together, the present series of experiments suggest an important role for spinal glial cells in the cascade of events that are initiated by descending signals following s.c. administration of formalin.

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