Opioids are commonly used for pain relief clinically and reduce hyperalgesia in most animal models. Two injections of acidic saline into one gastrocnemius muscle 5 days apart produce a long-lasting bilateral hyperalgesia without associated tissue damage. The current study was undertaken to assess the effects of opioid agonists on mechanical hyperalgesia induced by repeated intramuscular injections of acid. Morphine (-agonist (-agonist; U50,488) were administered intrathecally to activate opioid receptors once hyperalgesia was developed. Mechanical hyperalgesia was assessed by measuring the withdrawal thresholds to mechanical stimuli (von Frey filaments) before the first and second intramuscular injection, 24 h after the second intramuscular injection, and for 1 h after administration of the opioid agonist or vehicle. Morphine, DAMGO, and SNC80 dose dependently increased the mechanical withdrawal threshold back toward baseline responses. The reduction in hyperalgesia produced by morphine and DAMGO was prevented by H-D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH 2 (CTAP) and that of SNC80 was prevented by naltrindole. U50,488 had no effect on the decreased mechanical withdrawal thresholds. Thus, activation of -and ␦-, but not -, opioid receptors in the spinal cord reduces mechanical hyperalgesia following repeated intramuscular injection of acid, thus validating the use of this new model of chronic muscle pain.Chronic musculoskeletal pain is associated with significant disability and costs approximately 150 billion dollars per year in medical expenses within the United States alone (McCain, 1994;Yelin and Callahan, 1995). Musculoskeletal pain syndromes such as fibromyalgia and myofascial pain syndrome can be difficult to treat (McCain, 1994). For this reason, a new animal model of chronic muscle-induced pain was developed to examine mechanisms of chronic pain development and maintenance (Sluka et al., 2001b). Specifically, two injections of acidic saline into one gastrocnemius muscle 2 to 5 days apart produce a long-lasting bilateral hyperalgesia without associated tissue damage and without continued primary afferent input (Sluka et al., 2001b). This bilateral mechanical hyperalgesia is reversed by blockade of spinal NMDA or non-NMDA glutamate receptors (Skyba et al., 2002). Thus, this model produces a secondary mechanical hyperalgesia dependent on changes in the central nervous system.Opioids are commonly used for pain relief clinically (Miyoshi and Leckband, 2001) and reduce hyperalgesia in most animal models (Millan, 1986;Sabbe and Yaksh, 1990). There are three opioid receptors located in the spinal cord, , ␦, and , that when activated result in analgesia and a reduction in hyperalgesia (Millan, 1986). Following peripheral inflammation, there is an increased sensitivity to opioids in the spinal cord (Hylden et al., 1991b;Przewlocka et al., 1991;Stanfa et al., 1992). In contrast, in peripheral neuropathic pain, the sensitivity to opioids is greatly reduced (Ossipov et al., 1995). The hyperalgesia associated wi...