Abstract
Painful conditions are a huge medical burden with an estimated prevalence of 32% of the population, and an economic cost of $635 billion, or 4% of the GDP. Currently, the best available medical analgesics are opioids, but due to their vast side effect profile and risk of overdose, these are far from ideal drugs. Recently, the study of genetic mutations leading to congenital insensitivity to pain (CIP) has resulted in submission of novel drugs to the FDA for clinical trial. Here, we show our work on one such mutation of the gene Prdm12. We first characterized the expression pattern of Prdm12 within different sensory neurons present in the dorsal root ganglia (DRG) by performing in-situ hybridization paired with immunohistochemistry, and found it to be expressed in both myelinated and unmyelinated small-diameter axons of the thoracic and lumbar DRGs. We then generated a new strain of mice in which Prdm12 has been conditionally knocked out of neurons in DRG and cranial ganglia, and subjected these mice to a variety of behavioral assays alongside littermate controls. We have shown that the Prdm12cKO mice have reduced sensitivity to nociceptive thermal and mechanical stimuli, and correlated this with a decrease in the number of pain-sensitive IB4+ and CGRP+ Aδ and C fibers in the DRG. We believe that further study of this mouse model, along with investigation of the downstream effectors and genomic targets of PRDM12, will provide a new avenue for the pursuit of analgesic drug discovery.
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