TRPM8: From Cold to Cancer, Peppermint to Pain

Abstract

Temperature perception is vital for cellular and metabolic homeostasis, avoidance, and survival. In the primary afferent nerve terminal, select members of the transient receptor potential (TRP) family of ion channels reside and convert thermal stimuli into neuronal activity. The cold and menthol receptor, TRPM8, is the predominant thermoceptor for cellular and behavioral responses to cold temperatures. Remarkably, this single molecular sensor of cold, that responds at a discrete thermal threshold in vitro (approximately 28°C), enables sensory afferents to respond to distinct, yet varied thermal thresholds (approximately 28 to <5°C). Thus, unlike other thermally-gated TRP channels which are activated at either innocuous or noxious temperatures, TRPM8 provides perception of both pleasantly cool and painfully cold. In addition to this diversity in sensory signaling, TRPM8 has an emerging role in a variety of biological systems, including thermoregulation, cancer, bladder function, and asthma. Here we summarize some key points related to TRPM8 and its potential as a drug target to treat a wide variety of physiological conditions. Nonetheless, it remains to be seen how this single "cool" molecule can serve in such a multitude of biological processes.

Transient receptor potential (TRP) channels, promising potential diagnostic and therapeutic tools for cancer

“…TRPM8 is the predominant thermoceptor for cellular and behavioral responses following exposure to cold temperatures (19). This thermoceptor has been studied in different contexts, including breast adenocarcinoma, lung adenocarcinoma, melanoma, and prostate cancer (20).…”

Inflammatory and neuropathic cold allodynia are selectively mediated by the neurotrophic factor receptor GFRα3

“…The result can be an exacerbation of pain in response to both innocuous (allodynia) and noxious (hyperalgesia) stimuli (1). For example, pain felt with normally pleasant mild cooling (cold allodynia) occurs in many pathological conditions, such as fibromyalgia, multiple sclerosis, stroke, and chemotherapeutic-induced polyneuropathy, but what underlies this specific form of pain at the cellular or molecular level is largely unknown (2)(3)(4)(5). Pain-sensing afferent neurons (nociceptors) are sensitized during injury or disease, in part, by a vast array of proalgesic compounds termed the "inflammatory soup" (e.g., neurotrophic factors, protons, bradykinin, prostaglandins, and ATP) (1).…”

The Role of TRP Channels in Migraine

“…It is expressed in small-diameter primary sensory neurons, but co-localization studies are not in agreement as some report co-expression with other nociceptive markers (TRPV1 and CGRP) while others do not (for more references, see Knowlton and McKemy (2011) [148]. TRPM8 appears to be more highly expressed in trigeminal ganglia than dorsal root ganglia [40] and within trigeminal ganglia it is more abundant in the region of mandibular branch input.…”