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.