Characterization of the Lysophosphatidic Acid Receptor 5 Antagonist RLPA ‐76 as a Novel Analgesic in Male Rats and Mice

Clinically used analgesics such as gabapentinoids and opioids have limited efficacy and adverse effects like abuse liability, and there is a dire need for novel analgesics with improved safety profiles. Since lysophosphatidic acid can induce neuropathic pain in rodents, LPA receptor antagonists have been investigated as potential analgesics. This study examined the antiallodynic, reinforcing, and cognitive effects of lysophosphatidic acid receptor 5 (LPA5) antagonist, RLPA-76, using male rodents. Three preclinical pain models were used: spinal nerve ligation (SNL), chronic constriction injury (CCI), and complete Freund's adjuvant (CFA), where mechanical hypersensitivity was measured using von Frey filaments. Rats with a prior history of self-administering methamphetamine were allowed to self-administer RLPA-76 to assess abuse potential. To determine whether RLPA-76 had any cognitive effects, rodents were tested using novel object recognition (NOR) and T-maze. Platelet aggregation and radioligand binding screens were performed to evaluate drug specificity. RLPA-76 attenuated mechanical allodynia in SNL mice, CCI rats, and CFA rats. Rats self-administered RLPA-76 no more than vehicle, RLPA-76 pretreated mice performed like vehicle-treated mice in NOR, and CFA rats pretreated with RLPA-76 alternated to a similar extent to vehicle-pretreated rats in the T-maze. In vitro screens found that RLPA-76 lacked concentration-dependent effects on human platelets and had significant binding at only 1 of 44 targets. In conclusion, RLPA-76 was antiallodynic in multiple preclinical pain models and had no reinforcing or cognitive effects at analgesic doses in male rodents, supporting the therapeutic potential of RLPA-76 as a novel analgesic.