Contributions of peripheral and central opioid receptors to antinociception in rat muscle pain models Eva M a Sánchez ⁎, Ana Bagües, M a Isabel Martín Departamento de Farmacología y Nutrición. Facultad de Ciencias de la Salud, Universidad Rey Juan Carlos, Spain abstract article info Article history: Received 26 March 2010 Received in revised form 17 June 2010 Accepted 9 July 2010 Available online 15 July 2010 Keywords: Muscular pain Masseter Gastrocnemius Triceps Opioid Hypertonic saline Administration of hypertonic saline (HS) is an accepted model to study muscular pain. HS-induced nociceptive responses were tested in masseter, already described, and in two new pain models of spinally innervated muscles (gastrocnemius and triceps) developed in rats at our laboratory. HS administration in the masseter induced vigorous hindpaw shaking and in the gastrocnemius or triceps, paw withdrawal or flexing. Participation of the central and peripheral opioid receptors in HS-induced pain is compared in these muscles: masseter, innervated by trigeminal nerve, and gastrocnemius and triceps by spinal nerves. Morphine and loperamide were used to reveal peripheral and central components of opioid analgesia. Both agonists reduced HS-induced nociceptive behaviours in the masseter and were antagonised by the opioid antagonist naloxone and by naloxone methiodide, an opioid receptor antagonist that poorly penetrates the blood–brain barrier. Unexpectedly, in the gastrocnemius and triceps, morphine, but not loperamide, decreased the nociceptive behaviour and this effect was only reversed by naloxone. So, peripheral opioid receptors seem to participate in HS-induced masseter pain, whereas only central opioid receptors reduced the nociception in gastrocnemius and triceps. Our results suggest that the use of peripheral opioids can be more advantageous than central opioids for treatment of orofacial muscular pain. © 2010 Elsevier Inc. All rights reserved. 1. Introduction Muscle pain is the major presenting symptom of many clinically defined conditions. The economic and emotional impact of chronic musculoskeletal pain disorders may be measured in terms of lost productivity and human suffering. Since a muscle pain model consisting in an intramuscular (i.m.) injection of hypertonic saline (HS) (Kelgren, 1938) was introduced, this and similar models have been used to study human and animal experimental muscle pain (Graven-Nielsen, 2006; Capra and Ro, 2004; Mense, 2009). Muscle injection of exogenous agents activates nociceptive pathways producing reliable nocifensive behaviours (Sluka et al., 2002; Nielsen et al., 2004; Yokoyama et al., 2007). There are studies related to muscular pain models based on the assessment of behaviours induced by the i.m. administration of algesic agents into masseter, a craniofacial muscle (Shinoda et al., 2008; Ro et al., 2009) or into gastrocnemius or triceps, spinally innervated muscles (Kehl et al., 2000; Capra and Ro, 2004; Fujii et al., 2008). However, there are no data comparing muscle pain induced in the orofacial region with that induced in spinally innervated muscles. It is accepted that pain in the craniofacial territory, mainly innervated by the trigeminal nerve, presents some specific character- istics, such as a very complex anatomical and physiological organi- zation, and different nociceptive pathways. Some differences described between trigeminal and spinal innervations (Dood and Kelly, 1991; Sessle, 2005; Takemura et al., 2006; Burgos et al., 2010) are: - The infraorbital and maxillary branches of the trigeminal nerve are actually purely sensory nerves whereas the sciatic nerve is a mixed nerve and contains a significant motor component. - There is practically no functional overlap between the territory of the three branches of the trigeminal nerve, and they innervate a well defined and restricted region of the face which is very different from the spinal nociceptive innervation. - Differences in the analgesic effect of several drugs have been described. Moreover, to our knowledge, there is no algesic agent that has been used in both locations, in the same study, to permit an easy and reliable comparison of the results. Therefore, our first aim was to establish a model of experimental pain using HS that could be useful in the evaluation of acute muscular pain in the orofacial region (masseter), as well as in spinally innervated muscles (gastrocnemius and triceps). For this, we tested the HS effect in a masseter model already described (Ro et al., 2003) Pharmacology, Biochemistry and Behavior 96 (2010) 488–495 ⁎ Corresponding author. Facultad Ciencias de la Salud, Departamento de Farm- acología y Nutrición, Universidad Rey Juan Carlos. Avda. Atenas, s/n. 28922 Alcorcón, Madrid, Spain. Tel.: + 34 914888624; fax: + 34 914888955. E-mail address: eva.sanchez@urjc.es (E.M. Sánchez). 0091-3057/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.pbb.2010.07.009 Contents lists available at ScienceDirect Pharmacology, Biochemistry and Behavior journal homepage: www.elsevier.com/locate/pharmbiochembeh