Neuropathic pain (NeuP) affects >16 million Americans and results in considerable impairment in quality of life. Available medications fail to adequately relief pain in the majority of NeuP patients; moreover, efficacious drugs such as opioids have major safety concerns. Therefore, new therapeutic approaches are urgently needed. Serotonergic 5-HT3 receptors (5-HT3R) have been identified as a promising pharmacological target in NeuP. After peripheral nerve damage, overexpression of 5-HT3 receptors in spinal cord neurons can shift the character of descending serotonergic modulation from inhibitory to facilitatory, thus contributing to ongoing pain. Intrathecal 5-HT3R antagonists alleviate evoked hypersensitivity in animal NeuP models, but the analgesic effects are inconsistent with systemic administration of these drugs in patients with neuropathic pain. Our preliminary data suggest that efflux transporters such as the P-glycoprotein (Pgp) limit the central nervous system (CNS) exposure of 5-HT3R antagonists, thus preventing analgesia following systemic administration. We hypothesize that if 5-HT3R antagonists were to reach adequate CNS concentrations, they would be efficacious in relieving neuropathic pain. To validate 5-HT3R as a clinically-relevant drug target in neuropathic pain, we plan to undertake the following translational approach: 1) We will characterize the CNS disposition of model 5-HT3R antagonsits ondansetron and granisteron in a rat model, and determine the effect of efflux transporters such as Pgp on their CNS disposition. This will be done by a) determining drug bio-disposition in rat plasma and cerebrospinal fluid (CSF), as well as in brain and spinal cord (whole tissue analysis and micro-dialysis), and b) utilizing genetic and pharmacological knockouts of Pgp transporters to determine the effects of efflux transporters on drug disposition. 2) We will determine the role of Pgp efflux on ondansetron disposition in human CNS. This will be done by detemining the time-course of plasma and CSF concentrations of IV ondansetron in healthy subjects, with and without tariquidar? a selective inhibitor of Pgp transporters. Analgesia will be assessed in an experimental pain model, and physiologically-based pharmacokinetic modeling will be implemented to predict ondansetron concentrations in human brain and spinal cord, based on combined results from animal and human studies. 3) We will determine the effect of adequately CNS-penetrating ondansetron on neuropathic pain. In an experimental cross-over study in NeuP patients, analgesia will be compared when ondansetron is administered with and without tariquidar. In an exploratory mechanism-based analysis, we will determine the association between the extent of individual descending pain facilitation and the analgesic response to 5-HT3R blockade. We expect the results to successfully determine the mechanisms limiting CNS exposure of 5-HT3R antagonists, and to demonstrate that by bypassing these mechanisms, 5-HT3R antagonists can alleviate neuropathic pain, particularly in patients with sensory phenotype suggesting descending facilitation.
More than 16 million Americans suffer from neuropathic pain. Available medications fail to provide adequate pain relief in about two thirds of these patients, and many efficacious drugs such as opioids cause substantial toxicity. The proposed project aims to apply translational research methodology for determining the analgesic potential of enhanced delivery of 5-HT3 receptor antagonists to the central nervous system. This approach will provide a validation of 5- HT3 receptors as a clinically-relevant pharmacological target for neuropathic pain, thus providing the basis for the development of new, non-opioid drugs for improving outcomes in patients suffering from neuropathic pain.
