THE ROLE OF W-OPIOID RECEPTORS IN INFLAMMATORY HYPERALGESIA AND K2-ADRENOCEPTOR-MEDIATED ANTIHYPERALGESIA H. MANSIKKA, a L. ZHOU, b D. M. DONOVAN, b A. PERTOVAARA c and S. N. RAJA d a Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA b Transgenic Facility, IRP, NIA, NIH, Baltimore, MD, USA c Institute of Biomedicine, Department of Physiology, University of Turku, Turku, Finland d Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA AbstractöThe purpose of the present study was to investigate the role of W-opioid receptor in in£ammatory hyperalgesia in intact and in spinalized animals and the interaction between W-opioid and K2-adrenergic receptor in acute pain and in£ammatory hyperalgesia. Behavioral responses to mechanical and heat stimuli were studied in W-opioid receptor knockout mice and wildtype control mice. Thermal nociception was evaluated by measuring paw withdrawal latencies to radiant heat applied to the hindpaws. Mechanical nociception was measured by von Frey mono¢lament applications to the hindpaws. Intraplantar carrageenan-induced (1 mg/40 Wl) mechanical and heat hyperalgesia were compared in W-opioid knockout and wildtype mice. The e¡ect of systemically administered K2-adrenergic receptor agonist dexmede- tomidine (1^10 Wg/kg) was evaluated on mechanical and thermal withdrawal responses under normal and in£ammatory state in knockout and wildtype mice. The role of W-opioid receptor in descending modulation of nociception was studied by assessing mechanical and heat withdrawal responses before and after mid-thoracic spinalization. Withdrawal responses to radiant heat and von Frey mono¢laments were similar in W-opioid knockout and wildtype mice before and after the carrageenan induced hindpaw in£ammation. Also, antinociceptive e¡ects of dexmedetomidine in thermal and mechanical nociceptive tests were similar before carrageenan induced hindpaw in£ammation. However, the potency of dexmedetomidine was signi¢cantly reduced in carrageenan-induced mechanical hyperalgesia in W-opioid knockout mice compared to the wildtype control mice. Thermal and mechanical withdrawal responses were similar between W-opioid knockout and wildtype mice before and after mid-thoracic spinalization. Our observations indicate that the W-opioid receptors do not play an important role in K2-adrenergic receptor agonist- mediated acute antinociception. In addition, W-opioid receptors are not tonically involved in the modulation of in£am- mation-induced mechanical and thermal hyperalgesia, and the supraspinal control of spinal re£exes. However, in the presence of in£ammation, W-opioid receptors play an important role in the antihyperalgesic actions of an K2-adrenergic receptor agonist. ß 2002 IBRO. Published by Elsevier Science Ltd. All rights reserved. Key words: pain, allodynia, carrageenan, morphine, dexmedetomidine. Previous studies have demonstrated increased antinoci- ceptive potency of opioids during in£ammation. The increased potency is most pronounced for the W-opioid receptor (MOR) agonist morphine, whereas N- and U-opioid receptor agonists show only modest increase in potency during in£ammation (Kayser and Guilbaud, 1983; Hylden et al., 1991; Stanfa et al., 1992). The enhanced potency of opioids during in£ammation is thought to be mediated via peripheral, spinal and supra- spinal mechanisms (Stein et al., 1988; Hylden et al., 1991; Kayser et al., 1991; Stanfa et al., 1992; Hurley and Hammond, 2000). Previous studies have indicated that the endogenous opioid system is activated during in£ammation in the periphery and in the spinal cord contributing to the enhanced sensitivity to opiates (Iadarola et al., 1988; Millan et al., 1988; Hassan et al., 1993; Stein, 1995). In addition to activation of peripheral and spinal opioidergic antinociceptive mecha- nisms during in£ammation, descending inhibitory pain control mechanisms are also activated in in£ammatory pain (Ren and Dubner, 1996). The noradrenergic system is considered to be one of the major descending inhibi- tory pain control systems originating from the brainstem. Noradrenaline released from the descending axons con- trols the activity of nociceptive neurons in the dorsal horn (Peng et al., 1996; Cui et al., 1999). The MOR and K2-adrenergic receptor (K2-AR) are 339 *Corresponding author. Present address: Department of Anesthesi- ology, Turku University Hospital, P.O. Box 52, 20521 Turku, Fin- land. Tel.: +358-2-3130000; fax: +358-2-2502610. E-mail address: heikki.mansikka@tyks.¢ (H. Mansikka). Abbreviations: K2-AR, K2-adrenergic receptor; ANOVA, analysis of variance; KO, knockout; MOR, W-opioid receptor; WT, wild- type. NSC 5634 8-7-02 www.neuroscience-ibro.com Neuroscience Vol. 113, No. 2, pp. 339^349, 2002 ß 2002 IBRO. Published by Elsevier Science Ltd All rights reserved. Printed in Great Britain PII:S0306-4522(02)00189-6 0306-4522 / 02 $22.00+0.00