This presentation will provide a brief overview of the widening split between the advances in our understanding of the pathophysiological and cellular mechanisms of neuropathic pain (NP) and the clinical therapies for NP, which highlights the unmet needs from the patient and provider perspectives. A hypothesis will be presented that in many neuropathic pain conditions, the peripheral nervous system (PNS) is a promising target site for developing safe and efficacious new pharmacologic therapies. This view will be supported by neurophysiologic studies in humans suggesting that spontaneous and ectopic activity in the PNS may be the spark which is amplified in the CNS and kindles the wildfire that contributes to the development and maintenance of NP.  Additional evidence will be discussed, which indicates that blocking this peripheral input leads to pain relief in patients with chronic NP. Neurophysiologic studies in DRGs from patients with neuropathic pain and pluripotent stem cells from patients with small fiber neuropathy reprogrammed and differentiated into nociceptive neurons corroborate the evidence from microneurographic studies in humans.  Preclinical studies from Johns Hopkins investigators will be reviewed that provide evidence for a role of G-protein coupled receptors on peripheral sensory neurons, such as mu- opioid, cannabinoid, and mas-related G-protein coupled X1 receptors, in the modulation of excitability of nociceptors and alleviation of pain in animal models of partial nerve injury.  This work and that of many other investigators point to numerous GPCR targets on peripheral sensory neurons that may lead to novel, non-opioid, safe, and effective targets for NP treatment. The presentation will end on a note of optimism about our future that despite existing challenges, the scientific advances in the coming years is likely result in a stratified and personalized treatment for patients with neuropathic pain.



Learning Objectives
1. Articulate the unmet clinical needs in the treatment of neuropathic pain.
2. Formulate the pre-clinical and clinical evidence that sites on peripheral sensory neurons are attractive targets for the development of therapeutic strategies for neuropathic pain.
3. Determine the potential role of peripheral GPCR in modulation of pain and possible drug discovery targets for neuropathic pain.