TRPV1-Targeted Drugs in Development for Human Pain Conditions
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LEADING ARTICLE
TRPV1‑Targeted Drugs in Development for Human Pain Conditions Mircea Iftinca1 · Manon Defaye1 · Christophe Altier1
© Springer Nature Switzerland AG 2020
Abstract The transient receptor potential vanilloid-1 (TRPV1) is a non-specific cation channel known for its sensitivity to pungent vanilloid compound (i.e. capsaicin) and noxious stimuli, including heat, low pH or inflammatory mediators. TRPV1 is found in the somatosensory system, particularly primary afferent neurons that respond to damaging or potentially damaging stimuli (nociceptors). Stimulation of TRPV1 evokes a burning sensation, reflecting a central role of the channel in pain. Pharmacological and genetic studies have validated TRPV1 as a therapeutic target in several preclinical models of chronic pain, including cancer, neuropathic, postoperative and musculoskeletal pain. While antagonists of TRPV1 were found to be a valuable addition to the pain therapeutic toolbox, their clinical use has been limited by detrimental side effects, such as hyperthermia. In contrast, capsaicin induces a prolonged defunctionalisation of nociceptors and thus opened the door to the development of a new class of therapeutics with long-lasting pain-relieving effects. Here we review the list of TRPV1 agonists undergoing clinical trials for chronic pain management, and discuss new indications, formulations or combination therapies being explored for capsaicin. While the analgesic pharmacopeia for chronic pain patients is ancient and poorly effective, modern TRPV1-targeted drugs could rapidly become available as the next generation of analgesics for a broad spectrum of pain conditions.
1 Introduction Acute pain is a protective physiological response against harmful stimuli, such as extreme temperature, chemical irritants or tissue damage caused by injury or chronic inflammatory diseases [1]. Noxious or potentially noxious stimuli are transduced into nerve impulses by primary afferent neurons (nociceptors) and carried along the spinothalamic tract (Fig. 1) to reach the brainstem, thalamus and cerebral cortex, where nociceptive signals are encoded and perceived as painful. Pain that persists beyond the time of usual tissue healing (~ 3 months) is considered chronic [2] and is the most frequent reason for seeking consultations at primary care units. In the USA alone, estimated costs of chronic pain exceed US$600 billion annually [3]. Chronic pain can stem from nerve damage (neuropathic pain) often associated * Christophe Altier [email protected] 1
Department of Physiology and Pharmacology, Inflammation Research Network‑Snyder Institute for Chronic Diseases and Alberta Children’s Hospital Research Institute, Cumming School of Medicine, University of Calgary, 3330 Hospital Dr NW, Calgary, Alberta T2N 4N1, Canada
Key Points Pain is the most frequent reason for patients to seek medical care. Efforts have been made to design new nonopioid analgesics. Targeting the capsaicin receptor (TRPV1 channel) using ligands that cause defunctionalisation of “pain-sensing” n
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