Lysophosphatidic acid receptor 5 in insular cortex as a potential analgesic target in neuropathic pain

Neuropathic pain remains a significant clinical challenge and existing treatments have limited efficacy and often over rely on opioids. Pharmacological inhibition and genetic knockout of lysophosphatidic acid receptor 5 (LPA5) lead to an analgesic effect on nerve injury-induced nociceptive hypersensitivity in rodents. However, the specific pain-associated regions where LPA5 is required for neuropathic pain remain unidentified. Here, we demonstrate a site-specific increase in the levels of Lpa5 mRNA and LPA5 protein in the contralateral insular cortex and hippocampus 3-14 days after chronic constriction injury (CCI) of the unilateral sciatic nerve in mice. Blocking this time-dependent increase through microinjection of adeno-associated virus 5 (AAV5) expressing Lpa5 shRNA (AAV5-LPA5 shRNA) into insular cortex mitigated CCI-induced development of nociceptive hypersensitivities. This effect was not seen after microinjection of AAV5-LPA5 shRNA into the hippocampus. Mimicking this increase through microinjection of AAV5 expressing full-length Lpa5 mRNA into the insular cortex augmented responses to mechanical, heat and cold stimuli and induced ongoing pain in naïve mice. Moreover, systemic administration of selective LPA5 antagonist RLPA-76 alleviated CCI-induced mechanical allodynia and heat hyperalgesia. All treated mice displayed normal locomotor activities. Altogether, these findings suggest that LPA5 in the insular cortex plays a critical role in neuropathic pain genesis and support LPA5 as a potential target for neuropathic pain treatment.