The Antinociceptive Effects of Anticonvulsants in a Mouse Visceral Pain Model Radica M. Stepanovi ´ c-Petrovi ´ c, BPharm, PhD* Maja A. Tomi´ c, BPharm, MSc* Sonja M. Vuˇ ckovi ´ c, MD, PhD† Sonja Paranos, BPharm* Nenad D. Ugreši´ c, BPharm, PhD* Milica S ˇ . Prostran, MD, PhD† Slobodan Milovanovi ´ c, MD, PhD‡ Bogdan Boškovi ´ c, BPharm, MD, PhD‡ BACKGROUND: There is evidence supporting the antinociceptive effects of carbamaz- epine, oxcarbazepine, gabapentin, and topiramate in various models of neuropathic pain as well as inflammatory somatic pain. Data are lacking on the antinociceptive potential of these drugs against visceral pain. In this study, we examined and compared the effects of carbamazepine, oxcarbazepine, gabapentin, and topiramate in the writhing test as a visceral pain model in the mouse. In addition, the influence of these anticonvulsants on motor performance was examined to compare the tolerability of these anticonvulsants when used against acute visceral pain. METHODS: The antinociceptive effects of these anticonvulsants were examined in the acetic acid writhing test in mice. The side effect propensity of these drugs was examined using the rotarod test. RESULTS: Carbamazepine (25– 60 mg/kg; p.o.), oxcarbazepine (10 – 40 mg/kg; p.o.), gabapentin (10 –70 mg/kg; p.o.), and topiramate (5–30 mg/kg; p.o.) caused a significant dose-dependent reduction the number of writhes in the writhing test. In the rotarod test, carbamazepine (60 –140 mg/kg; p.o.) and oxcarbazepine (120 – 450 mg/kg; p.o.) significantly reduced the time spent on the rotarod in a dose- and time-dependent manner. Gabapentin (1000 –2000 mg/kg; p.o.) and topiramate (400 –1500 mg/kg; p.o.) did not produce significant impairment of motor perfor- mance at the highest doses used. The therapeutic index (motor impairing dose TD 50 /writhing ED 50 ) values were topiramate (148.5)  gabapentin (60.2)  oxcarbazepine (15.2)  carbamazepine (2.3). CONCLUSIONS: These results indicate that oxcarbazepine, gabapentin, and topiramate are effective in the writhing model in mice, in a dose range, which is not related to motor impairment; topiramate is the most potent and the most tolerable drug. (Anesth Analg 2008;106:1897–103) Visceral pain (e.g., angina, colic, dyspepsia, pan- creatitis, appendicitis, dysmenorrhea, hysterectomy, tumor invasion of viscera), caused by activation of nociceptors in viscera, constitutes a large portion of clinically treated pain. 1–3 If an inflammatory process or tissue injury occurs in internal organs, or if non-noxious stimuli are applied in a repeated and/or prolonged fashion locally, the visceral struc- tures may become hypersensitive. 1,4 In fact, intense activation of nociceptive primary afferent fibers by visceral tissue injury and inflammation produces central sensitization or hyperexcitability of nocicep- tive neurons in the spinal cord dorsal horn that contributes to hyperalgesia. 1 Intraperitoneal administration of dilute acetic acid (AA) produces a characteristic writhing response in mouse. This behavior is considered to be evidence of peritoneovisceral pain, since AA directly activates visceral and somatic nociceptors innervating the peri- toneum and induces inflammation not only in subdia- phragmatic visceral organs, but also in subcutaneous muscle walls. 5 There is evidence that polymodal C fibers and A fibers are present in the gut. 5,6 AA causes tissue damage and releases pain-producing substances that activate nociceptors on the sensory nerve fibers. 7 Carbamazepine, oxcarbazepine, gabapentin, and topiramate are used as antiepileptic drugs and for treating the neuropathic pain. 8,9 There is evidence of the antinociceptive effects of carbamazepine, oxcarba- zepine, gabapentin, and topiramate in various models of neuropathic pain. 10 –13 Substantial experimental data have been provided on the antinociceptive effects of carbamazepine, oxcarbazepine, and gabapentin in models of inflammatory somatic pain after sys- temic, 11,14 –17 as well as local peripheral administra- tion. 18 –21 Topiramate did not produce statistically significant analgesic effects in models of inflammatory somatic pain after systemic administration, 15 but there are no data after local peripheral administration. From the *Department of Pharmacology, Faculty of Pharmacy, †Department of Pharmacology, Clinical Pharmacology and Toxicol- ogy, Faculty of Medicine, University of Belgrade, and ‡Military Medical Academy, Belgrade, Serbia. Accepted for publication February 7, 2008. Supported by grants of Ministry of Science of Serbia (No. 145030 and 145001). Address correspondence and reprint requests to Radica M. Stepanovi ´ c-Petrovi ´ c, BPharm, PhD, Department of Pharmacology, Faculty of Pharmacy, Vojvode Stepe 450, POB 146, 11221 Belgrade, Serbia. Address e-mail to racabbr@eunet.yu. Copyright © 2008 International Anesthesia Research Society DOI: 10.1213/ane.0b013e318172b993 Vol. 106, No. 6, June 2008 1897