We evaluated the effects of s 1 -receptor inhibition on m-opioidinduced mechanical antinociception and constipation. s 1 -Knockout mice exhibited marked mechanical antinociception in response to several m-opioid analgesics (fentanyl, oxycodone, morphine, buprenorphine, and tramadol) at systemic (subcutaneous) doses that were inactive in wild-type mice and even unmasked the antinociceptive effects of the peripheral m-opioid agonist loperamide. Likewise, systemic (subcutaneous) or local (intraplantar) treatment of wild-type mice with the selective A peripheral role for s 1 receptors was also supported by their higher density (Western blot results) in peripheral nervous tissue (dorsal root ganglia) than in several central areas involved in opioid antinociception (dorsal spinal cord, basolateral amygdala, periaqueductal gray, and rostroventral medulla). In contrast to its effects on nociception, s 1 -receptor inhibition did not alter fentanyl-or loperamide-induced constipation, a peripherally mediated nonanalgesic opioid effect. Therefore, s 1 -receptor inhibition may be used as a systemic or local adjuvant to enhance peripheral m-opioid analgesia without affecting opioidinduced constipation.

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