Integrative And Molecular Studies Of Pain And Pain Control

Clinical Center

Investigators

Linked publications, trials & patents

Abstract

Overview: This research program addresses basic molecular and physiological processes of nociceptive (pain-sensing) transmission in the peripheral and central nervous systems (CNS) and new ways to effectively control pain. The molecular research is performed on human tissue to facilitate translational potential. We concentrate on primary afferent pain-sensing neurons located in dorsal root ganglion (DRG) that send axonal projections peripherally to skin and deep tissues and at their central end make connections with neurons in the dorsal spinal cord. This is the first CNS site of synaptic information processing for pain. In this cycle we also initiated intensive spatial transcriptomic analyses of spinal cord dorsal horn. Our goals are (a) to understand the molecular and cell biological mechanisms of acute and chronic pain at the initial steps in the pain pathway, (b) to investigate mechanisms underlying human chronic pain disorders, (c) to explore neuronal plasticity and altered gene expression in persistent pain states. The overarching goal is to use new knowledge to devise new treatments for pain. New Treatments for Pain: We address the new treatment goal through translational research coupled with human clinical trials to develop and introduce effective molecular interventions for treating severe pain. In this cycle we published our interim Phase I human clinical trial results with the TRPV1 agonist resiniferatoxin (RTX) to treat intractable pain in patients with advanced cancer. We also completed a second RTX Phase I clinical trial to treat neuropathic pain from a nerve injury. Agonist activation of TRPV1 causes an influx of sodium and calcium ions through the pore of TRPV1. The unique property of RTX for therapeutic purposes is its pseudo-irreversible binding to TRPV1 which props open the ion channel causing an intracellular calcium overload and cytotoxicity. Depending on the route of administration, RTX disables TRPV1 pain-sensing nerve endings or axons (i.e., the nerve fiber) or deletes the neuron entirely when applied near the neuronal perikarya. At the same time, non-TRPV1 expressing neurons are not affected by RTX, thereby sparing most forms of somatosensation and motor function. In the human cancer clinical trial, we administer RTX into the lumbar CSF (intrathecal) and we observed significant reduction in pain rating and reduction in opioid consumption with a single injection. This is ideal for palliative care where minimal impact on the patient is an important goal. The neuropathic pain trial in Morton neuroma pain used perineural infiltration around the nerve just proximal to the neuroma. RTX basically outperformed our expectations: We completed the protocol at the first dose tier by reaching the ED100 in the first three patients. We are now planning a Phase II study. The DPM is exploiting the success of the perineural application in a new clinical protocol to treat pain from thoracic surgery. We plan to administer RTX perineurally to the intercostal nerves. We hypothesize that this will block the tissue damage pain from the thoracotomy procedure which is notoriously difficult to control. During this cycle we have made a strong effort to incorporate direct in human studies of nociceptive molecular biology into the translational program. This was prompted by our repeated observations of species differences in gene expression in dorsal root ganglion (DRG) and spinal cord. Human skin, nerve, DRG and spinal cord tissues are recovered from organ donors or obtained by at autopsy of NIH patients. These tissues are being analyzed intensively by whole tissue sequencing and advanced spatial transcriptomic in situ hybridization methods for mRNAs and by and immunofluorescence staining for proteins. This is a powerful approach. For example, in spinal cord we identified a distinct population of spino-thalamic projection neurons. Ascertainment of the receptor complement in these neurons has suggests new ways to pharmacologically inhibit the transmission of painful information from spinal cord to brain and potentially new analgesics. Basic Pain Mechanisms: Underlying the translational and clinical studies are investigations of neuronal function, behavior, molecular biological mechanisms of pain transduction and human genetic variations that affect pain sensitivity. In the previous cycle we completed a study of a group of rare individuals with a copy number variant (CNV) involving the gene locus 7q11.23. Individuals with three copies of this ~1.5 megabase region exhibit profound decreases in pain sensitivity. Using RNA-Seq we identified one gene, STX1A, in the CNV (which in total contains 25 genes) that is an excellent candidate for mediating analgesic actions when overexpressed. The results define a previously unidentified genetic mechanism governing pain sensitivity. We are now examining the effect that developing without a sense of pain has on human brain structure and connectivity. This type of investigation has not been possible to date. The syntaxin mechanism we discovered represents a new candidate target for development of analgesic agents.