364 The positive allosteric modulator BMS-122 increases the efficacy of opioid and non-opioid analgesics neuropathic pain

Objectives/Goals: Opioids treat pain but with the risk of severe adverse effects. The opioid positive allosteric modulator BMS-122 has been shown to enhance opioid antinociception in animal models without increasing adverse effects. However, whether BMS-122 is effective in chronic neuropathic pain is unknown. Methods/Study Population: We used two animal models: spared nerve injury (SNI) and tibial neuroma. Injuries were performed on male and female Sprague-Dawley rats. Animals developed robust sensitivity to tactile stimulation similar to that seen in patients. Animals with SNI received the mu-opioids methadone, morphine, and buprenorphine, or gabapentin (30 mg/kg, s.c.), with or without BMS-122 (10 mg/kg, s.c.). Tactile hypersensitivity was measured using von Frey filaments. Animals with tibial neuroma received methadone (s.c.) with or without BMS-122 (10mg/kg s.c.), and tactile hypersensitivity was measured using a modified Tinel’s test, in which the neuroma was directly stimulated. Results/Anticipated Results: Hypersensitivity following SNI was reversed with administration of high-dose opioids or gabapentin. Following pre-treatment with BMS-122 low, ineffective doses of opioid or gabapentin significantly reversed the hypersensitivity. Buprenorphine was unable to fully reverse the hypersensitivity alone but was fully efficacious in the presence of BMS-122. Animals with tibial neuroma developed hypersensitivity at the neuroma site, but the doses of methadone required to reverse this sensitivity also induced respiratory depression. In the presence of BMS-122, a low, non-effective, dose of methadone reversed hypersensitivity without depressing breathing. No sex differences were observed in either condition. Discussion/Significance of Impact: These data show that positive allosteric modulators like BMS-122 provide an opioid-sparing effect in chronic neuropathic pain. Furthermore, BMS-122 appears to enhance endogenous opioid peptides to increase the effectiveness of non-opioid analgesics. Overall, these data support the continued development of modulators as therapeutics.