Nerve Injury Induces a Tonic Bilateral μ-Opioid Receptor-mediated Inhibitory Effect on Mechanical Allodynia in Mice

Background: Mice lacking the μ-opioid receptor gene have been used to characterize the role of μ-opioid receptors in nociception and the analgesic actions of opioid agonists. In this study, the authors determined the role of μ-opioid receptors in neuropathic pain behaviors and the effectiveness of μ- and κ-opioid receptor agonists on this behavior in mice. Methods: The authors studied the behavioral responses of μ-opioid receptor knockout and wild-type mice to thermal and mechanical stimuli before and after neuropathic pain induced by unilateral ligation and section of the L5 spinal nerve. Response to mechanical stimuli was evaluated by determining the frequency of hind paw withdrawal to repetitive stimulation using a series of von Frey monofilaments. Thermal hyperalgesia was assessed by determining the paw withdrawal latencies to radiant heat and frequency of hind paw withdrawal to cooling stimuli. The effects of systemic morphine, the κ-opioid agonist U50488H, and naloxone on responses to mechanical and thermal stimuli were also studied in spinal nerve-injured mice. Results: After spinal nerve injury, wild-type mice developed increased responsiveness to mechanical, heat, and cooling stimuli ipsilateral to nerve injury. μ-Opioid receptor knockout mice not only had more prominent mechanical allodynia in the nerve-injured paw, but also expressed contralateral allodynia to mechanical stimuli. Hyperalgesia to thermal stimuli was similar between μ-opioid knockout and wild-type animals. Morphine decreased mechanical allodynia dose dependently (3-30 mg/kg subcutaneous) in wild-type mice-an effect that was attenuated in the heterozygous mice and absent in the homozygous μ-opioid knockout mice. The κ-opioid agonist U50488H (3-10 mg/kg subcutaneous) attenuated mechanical allodynia in wild-type, heterozygous, and homozygous μ-opioid mice. Naloxone in wild-type mice resulted in enhanced ipsilateral and contralateral allodynia to mechanical stimuli that resembled the pain behavior observed in μ-opioid receptor knockout mice. Conclusions: The authors' observations indicate that (1) unilateral nerve injury induces a bilateral tonic activation of endogenous μ-opioid receptor-mediated inhibition that attenuates mechanical allodynia but not thermal hyperalgesia, (2) both μ- and κ-opioid agonists attenuate neuropathic pain in mice, and (3) the antihyperalgesic actions of morphine are mediated primarily via μ-opioid receptors.