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BEHAVIORAL PHARMACOLOGY

Acetazolamide, a Carbonic Anhydrase Inhibitor, Reverses Inflammation-Induced Thermal Hyperalgesia in Rats

Department of Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences, Pomona, California (R.R.); and Graduate Program in Physical Therapy and Rehabilitation Science, Pain Research Program, and Neuroscience Graduate Program, University of Iowa, Iowa City, Iowa (K.A.S.)

Inflammatory pain is linked to reduction in tissue pH. Tissue proton generation is mainly mediated by carbonic anhydrases (CAs). We therefore hypothesized that inhibition of CAs with acetazolamide (ACTZ) increases the tissue pH and reverses inflammation-induced pain. CAs are also present in the central nervous system and control anion concentrations. Furthermore, ACTZ has direct effects on ion channels involved in nociception. In the current study, responses to heat and mechanical stimuli (von Frey filaments) of the paw were assessed before and after carrageenan-induced muscle inflammation and after treatment with ACTZ in rats. ACTZ was administered systemically, locally, or intrathecally 24 h after the induction of inflammation. In separate studies, pH was measured in the inflamed and noninflamed muscles and after administration of ACTZ. Carrageenan injection to the gastrocnemius muscle produced heat hyperalgesia and mechanical allodynia of the paw. Systemic ACTZ reversed the heat hyperalgesia but not mechanical allodynia. Similarly, injections of ACTZ into the inflamed muscle or intrathecally reversed the heat hyperalgesia but not mechanical allodynia. Surprisingly, the pH in the inflamed muscle was not reduced compared with noninflamed muscle. Thus, the current data do not support our hypothesis that ACTZ reduces inflammatory hyperalgesia by raising the reduced pH in muscle. Although the possibility of pH changes and the role of CAs in the microenvironment cannot be ruled out, the mechanism of ACTZ-induced antihyperalgesia is not clear from this study. It is possible that the inhibition of ion channels and/or the inhibition of spinally located CAs contribute to the observed antihyperalgesia.

Address correspondence to: Dr. Kathleen A. Sluka, Graduate Program in Physical Therapy and Rehabilitation Science, 1-252 Medical Education Building, University of Iowa, Iowa City, IA 52242-1190. E-mail: kathleen-sluka{at}uiowa.edu