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Chronic pain affects a large segment of the population, an estimated 50 million Americans, and costs the country billions of dollars in health care costs and lost productivity. Although the Decade of Pain Control and Research has given new impetus to pain research, the translation of preclinical research into clinical practice is slow to occur. This is evident by the limited number of mechanistically novel therapeutic agents that have entered into the clinic for the treatment of pain in recent years. Consequently, agents that have been around for decades such as opiates and nonsteroidal anti-inflammatory drugs (NSAID) still represent a mainstay in the current pain therapy. However, NSAIDs have only modest effects on moderate to severe pain and their use is limited by a combination of gastrointestinal and cardiovascular side effects. Clearly, new potent analgesic drugs with an acceptable safety profile are needed.
Transient Receptor Potential (TRP) channels (so-called “thermoTRPs”) on nociceptive neurons is a particularly attractive strategy in that it targets the beginning of the pain pathway. TRP channels serve diverse afferent (transduction of mechanical, chemical, thermal stimuli) and efferent (e.g. growth control, cellular differentiation, thermoregulation, vasoregulation and mediator release) functions. These TRP channel properties may be exploited therapeutically. And in the focus of current drug development efforts are the heat-sensitive TRPV1, warm-activated TRPV3, cold-responsive TRPA1, and cool-activated TRPM8 channels.
The role of TRPM8 as a cold sensor
The transient receptor potential melastatin 8 (TRPM8) protein is a member of the TRP superfamily of ion channels which are known to perform a myriad of functions in vertebrates and invertebrates alike. TRPM8 is encoded by a cDNA with an open reading frame of 3312 nucleotides which code for a protein of 1104 amino acids with a molecular weight of 128 kDa. Like all TRP channels, TRPM8 forms a six-pass transmembrane protein, with a long segment between transmembrane domains S5 and S6 forming a putative pore loop of this tetrameric protein. Less than ten years ago, TRPM8 was first reported as a specific marker for prostate cancer cells (then deemed Trp-p8) and shortly thereafter as a cold- and menthol-receptor in sensory neurons (also called CMR1).
The Xenopus laevis clone of TRPM8 was recently reported, and its presence in a non-mammalian, cold-blooded vertebrate and activation threshold of 15°C was interpreted to mean that TRPM8 may play an important role in vertebrate body temperature set points. However, dogs, with body temperatures exceeding 38°C, have a version of TRPM8 activated around 17°C, indicating that this generalization may be more nuanced than proposed. Nevertheless, systemic icing administration induces a dose dependent hyperthermia that is initiated outside of the brain, as well as autonomic and active thermoregulatory behaviors. TRPM8 has recently been implicated in the regulation of overall vascular tone and vasodilation, which could affect body temperature and blood circulation.
Targeting TRPM8 to relieve cold allodynia
In addition to mediating normal thermosensation, TRPM8 is involved in both cooling-mediated analgesia and cold hypersensitivity after injury. Activation of TRPM8 by icing or mild cooling in the context of neuropathic injury increases thermal and mechanical pain thresholds, an effect that is lost when TRPM8 expression is blocked with siRNA or when tested in TRPM8-null mice. TRPM8-null mice also fail to exhibit hypersensitivity to cold stimuli normally seen in models of inflammatory pain. TRPM8 expression levels are modulated in injury models as well as neuropathic pain patients.
● TRPM8 agonists
Cooling (e.g. ice-packs) is a time-honored analgesic approach to soothe acute pain secondary to skin burn or muscles trains. Menthol, a naturally occurringTRPM8 agonist isolated from peppermint leaves, has been used for centuries in folk medicine as an analgesic and antipruritic agent. Of note, menthol is also broadly used in lozenges, nasals prays, inhalers and cough syrups for the relief of nasal congestion associated with rhinitis and upper respiratory tract irritation, and it is added to certain cigarette brands to reduce the respiratory irritation that the smoke causes. A new potential novel therapeutic approach has arisen as a result of basic science findings from translational research group which demonstrated that endogenous neural circuitry underlying cooling-induced analgesia may represent a novel target for intervention. Researchers have identified how activation of one of these, the transient receptor potential melastatin TRPM8 ion channel, by topical agents, produced significant analgesia. As a result of the study, they successfully used topical menthol, a TRPM8 agonist, in two cases of treatment-resistant chemotherapy-induced peripheral neuropathy, allowing continuation of life prolonging treatment.
● TRPM8 antagonists
TRPM8 antagonists have the potential to induce hypothermia; an effect that has been demonstrated in preclinical species. A variety of small molecule TRPM8 antagonists covering a broad range of chemical and physical property space have been published in the literature. A study has identified PF-05105679, an antagonist of TRPM8, and a key clinical tool for exploring both the role of TRPM8 in regulating core body temperature and the potential of TRPM8 antagonists for the treatment of pain in humans. However further studies are required to understand if TRPM8 remains a viable target for the treatment of cold-related pain in patients.
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The discovery of the TRP channels has provided an opportunity for the development of analgesics, which are potentially more specific for certain pain syndromes and have a better side-effect profile than other interventions. TRP channels are being investigated as novel targets for drug discovery; they have a major advantage over more widely distributed voltage-sensitive ion channels, in their potential for achieving analgesia without overwhelming side effects in neuropathic pain. Menthol is a well-known and well-used analgesic, present in many over-the-counter drugs currently available, from cough drops to topical pain creams. However, in the case of chronic pain where application of TRPM8 agonists is not feasible or convenient or would lead to exacerbation of cold hypersensitivity, development of systemic TRPM8- antagonizing drugs may benefit patients by blocking these symptoms.
TRPM8 has been proved an important target in the treatment of cold hypersensitivity. And it also has the potential as a drug target to treat cancer. TRPM8 expression has been found in a number of other cancers, including melanoma, breast adenocarcinoma, colorectal cancer, lung cancer, and bladder cancer. In the cases of melanoma and bladder cancer, activation of TRPM8 by menthol leads to a dose-related decrease in cell viability. Menthol based anticancer drugs are an interesting possibility for treatment; however, as TRPM8 is implicated in survival of other types of cancer cells and metastatic disease, agonist based drugs might have an effect opposite of what is desired. Therefore a clearer picture of TRPM8 expression and the mechanism of its involvement in specific cancers need to be further elucidated.