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Mechanism-guided amelioration of hyperactivity in human and rodent nociceptors linked to spontaneous pain

Award Number: RF1NS144915
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/21/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2029

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Mechanism-guided amelioration of hyperactivity in human and rodent nociceptors linked to spontaneous pain - Project Summary The long-term objective of this project is to discover novel, highly targeted approaches for treating ongoing or spontaneous human pain that minimizes adverse side effects. It builds on accumulating evidence that ongoing pain is driven – to a far greater extent than previously recognized – by persistent spontaneous or ongoing electrical activity generated in sensory neurons that detect injury and inflammation, nociceptors. This ongoing activity (OA) is termed spontaneous activity (SA) when generated by mechanisms intrinsic to an active neuron, and OA more generally (e.g., when persistent activity is driven by prolonged exposure to inflammatory mediators). In many cases, including in human patients with neuropathic pain, pain-associated OA is generated in the nociceptor cell body (soma). Fortuitously, somally generated OA induced by painful conditions in a person or rodent can persist after isolation of the nociceptor soma (removing it from the body and ganglion), and it is evident during recording with whole-cell patch clamp methods. These recordings reveal irregular, depolarizing spontaneous fluctuations of membrane potential (DSFs) that are critical for controlling the likelihood and pattern of OA induced by neuropathic conditions, surgical injury, and inflammation. This project extends recent progress defining the contributions of multiple ion channels to the generation of large DSFs that control the likelihood and pattern of OA. It will test the hypothesis that specific ion channels – including Nav1.8 and voltage-gated Ca2+ channels (VGCCs) – that are important for generating large DSFs and hyperexcitability can be targeted together by combinations of low concentrations of clinically relevant inhibitors to reduce ongoing pain. Mechanism-based predictions of this hypothesis will be tested using selected drugs and hyperactive human nociceptors. Drugs, including two that are FDA-approved for other uses and that have mechanisms of action that should reduce large DSFs and OA in nociceptors, will be tested with customized whole-cell patch methods on dorsal root ganglion neurons isolated from cancer patients with documented neuropathic pain distributions. The effects of a wide range of doses of ion channel blockers will be examined individually and in combination. In parallel studies, the prediction that combined blockers of Nav1.8 and VGCCs will suppress ongoing pain behavior will be tested using three quite different rodent models of clinically significant pain in which potentiation of DSFs and SA/OA is prominently involved: a central neuropathy model (rat spinal cord injury), a postsurgical pain model (rat extended plantar incision), and a chemotherapy model (mouse cisplatin treatment). This project will leverage basic knowledge about DSFs (a particularly important driver of pain-associated OA in nociceptors) to select and test novel drug combinations that offer promise for the improved treatment of spontaneous and ongoing pain.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $2,330,525 )
2026	2026	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON	7000 FANNIN ST FL 9	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	9/19/2026	NEW	$2,330,525
														Subtotal = $2,330,525

Grand Total All Awards = $2,330,525

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Mechanism-guided amelioration of hyperactivity in human and rodent nociceptors linked to spontaneous pain

Award Number: RF1NS144915

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/21/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2029

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