Peripheral neuropathic pain (NP) is a significant public health problem debilitating both patients and their families and has a substantial impact on the health care system. Over 50 million people suffer worldwide from diabetes-related neuropathic pain (DPN). The pain associated with diabetic nerve damage has been shown to involve the activity in heat-sensitive trpv1 nociceptors in the skin. For this reason a strategy wa developed to deplete these neurons by using the trpv1 agonist capsaicin. However capsaicin, as a chemical agonist at trpv1, has non-specific toxic effects, leading to painful inflammation and depletion of non-nociceptive neurons in the skin, such as those that transduce touch. Despite the fact that high concentration capsaicin patches generally do help with DPN, they have not achieved widespread use - in large part because of these non- specific toxicity issues. Thus, there is an unmet need for a specific trpv1 agonist that could be used to deplete nociceptor terminals in the skin without the adverse effects of capsaicin. The goal of the experiments proposed here is to determine whether diode laser (DL) pulses, which produce heat deep within the skin, will be able to not only activate these nociceptors, but also deplete them, and so produce analgesia. As heat is a non-chemical, and highly specific physical agonist for trpv1, this depletion should not require the off-target toxic effects that are observed with capsaicin treatments. Experiments described here use pigs, which have skin most similar to humans, as an experimental model to determine whether and to what extent, different doses of DL pulses can selectively and dose-dependently deplete cutaneous nerve fiber endings as indicated by decreased labeling with the neuronal markers PGP9.6/TRV1. These experiments will furthermore determine whether this depletion can be achieved without reaching surface temperatures which cause substantive skin damage as assessed by standard hematoxylin and eosin histological techniques. Surface temperatures will be monitored using a high-speed thermal camera to aid in this goal as well as to provide a basis for the late development of a next generation scanning DL device, which will incorporate temperature feedback. Thus, these experiments are intended to allow optimization of doses of DL irradiation that can be rapidly translated to human clinical testing and eventually to an important new tool for the treatment of patients with painful peripheral neuropathy.
Public Health Relevance Statement: Public Health Relevance: The long-term goal of this project is to develop a novel, non-pharmacologic approach to the treatment of peripheral neuropathic pain using a diode laser radiation. The experiments proposed here build on our expertise to enable rapid translation of this technology to patients.
NIH Spending Category: Bioengineering; Diabetes; Neurodegenerative; Neurosciences; Pain Conditions - Chronic; Pain Research; Peripheral Neuropathy
Project Terms: Ablation; Absence of pain sensation; Acute; Adverse effects; Affect; Agonist; Animals; base; Capsaicin; Chemicals; Clinical; cost; Cream; Cutaneous; density; Development; Devices; Diabetes Mellitus; diabetic; Diabetic Neuralgia; Diabetic Neuropathies; Diagnosis; Dose; experience; Experimental Models; Family; Family suidae; FDA approved; Feasibility Studies; Feedback; Goals; Half-Life; Healthcare; Healthcare Systems; Heating; Hematoxylin and Eosin Staining Method; Histological Techniques; Hour; Human; Hypersensitivity; Immunohistochemistry; improved; Inflammation; inflammatory pain; irradiation; Label; Lasers; Lead; Light; Marketing; Measures; Mechanics; Mediating; Methods; Monitor; Nerve; Nerve Endings; Nerve Fibers; nerve supply; Neurons; Neuropathy; next generation; Nociception; Nociceptors; novel; Pain; painful neuropathy; Patients; Peripheral; Peripheral Nervous System Diseases; Pharmacologic Substance; Phase; Physicians; Physiologic pulse; Pilot Projects; Placebos; Postherpetic neuralgia; Property; Protocols documentation; public health medicine (field); public health relevance; Quality of life; research clinical testing; research study; Rice; Scanning; Sensory; Severities; Skin; Small Business Innovation Research Grant; Source; Speed (motion); spontaneous pain; Supervision; Surface; Technology; Temperature; Testing; therapeutic target; tool; Touch sensation; Toxic effect; Translating; Translations; Treatment Cost; type I diabetic; Work
