Rishi Sharma

Transmission of pain in spinal cord to brain requires N-methyl-D-aspartate receptor (NMDAR) activity to transmit glutamatergic signaling between neurons. NMDAR activity is decreased due to opiates activating the mu-opioid receptor (MOR) in the short term. In the long term, a tolerance to this effect develops, which is a major contributor to dose escalation and subsequently the abuse of opiates. Cross-talk between MOR and NMDAR is mediated by histidine triad nucleotide-binding protein 1 (HINT1). HINT1 has not been studied in neuropathic pain states, a prolonged state of pain in which several mechanisms lead to continuous activity of NMDAR and thus the perception of pain. Depending on the role of HINT1 in neuropathic pain, HINT1 may be a promising target for alternatives to opiates in the treatment of pain. Here we show expression levels of HINT1 protein in mice induced to exhibit chronic neuropathic pain in spinal cord and dorsal root ganglia (DRG). While further testing is required, initial results indicate an increase of HINT1 expression in lumbar segment 3 DRG ipsilateral to nerve injury; this segment innervates the area of induced chronic pain. We also show a decrease in behavioral manifestation of chronic pain when these mice are injected intrathecally with HINT1 inhibitors. These data further solidify the logic of inhibiting HINT1 as a potential therapy for chronic pain. This information serves as a useful stepping stone to develop an alternative therapy to opiates for use in chronic pain.