Inhibition of TRPM8 Channels Reduces Pain in the Cold Pressor Test in Humans

Abstract

The transient receptor potential (subfamily M, member 8; TRPM8) is a nonselective cation channel localized in primary sensory neurons, and is a candidate for cold thermosensing, mediation of cold pain, and bladder overactivity. Studies with TRPM8 knockout mice and selective TRPM8 channel blockers demonstrate a lack of cold sensitivity and reduced cold pain in various rodent models. Furthermore, TRPM8 blockers significantly lower body temperature. We have identified a moderately potent (IC 50 5 103 nM), selective TRPM8 antagonist, PF-05105679It demonstrated activity in vivo in the guinea pig bladder ice water and menthol challenge tests with an IC 50 of 200 nM and reduced core body temperature in the rat (at concentrations .1219 nM). PF-05105679 was suitable for acute administration to humans and was evaluated for effects on core body temperature and experimentally induced cold pain, using the cold pressor test. Unbound plasma concentrations greater than the IC 50 were achieved with 600-and 900-mg doses. The compound displayed a significant inhibition of pain in the cold pressor test, with efficacy equivalent to oxycodone (20 mg) at 1.5 hours postdose. No effect on core body temperature was observed. An unexpected adverse event (hot feeling) was reported, predominantly periorally, in 23 and 36% of volunteers (600-and 900-mg dose, respectively), which in two volunteers was nontolerable. In conclusion, this study supports a role for TRPM8 in acute cold pain signaling at doses that do not cause hypothermia.

Essential Role of Transient Receptor Potential M8 (TRPM8) in a Model of Acute Cold-induced Urinary Urgency

“…E U R O P E A N U R O L O G Y X X X ( 2 0 1 5 ) X X X -X X X pharmacological inhibition of TRPM8. The first results for oral administration of a TRPM8 antagonist (PF-05105679) in humans show that the drug was well tolerated at doses that were effective in a cold pressor test [38]. Therefore, there are prospects for the development of TRPM8 antagonists for specific therapies to alleviate ACIU symptoms in LUTd patients.…”

Discovery of a Selective TRPM8 Antagonist with Clinical Efficacy in Cold-Related Pain

“…33,42 While not a direct measure of the compounds ability to act as an analgesic, the assay did provide a direct measure of TRMP8-mediated pharmacology. Results from these studies indicated that a maximum unbound concentration (C max ) of drug between 254− 450 nM (∼3 × IC 50 ) would be sufficient to test the mechanism in clinical studies.…”

Expression of TRPM8 in diabetic rats and its relationship with visceral pain stimulation

“…Additionally, TRPM8-immunoreactive staining has been observed in the urothelium and in nerve fibers distributed throughout the suburothelium, and a marked increase in the number of fine-caliber nerve fibers immunoreactive for TRPM8 was found in patients with BPS compared with controls (P < 0.05) (Mukerji et al, 2006). Furthermore, TRPM8 antagonists lower body temperature in rats, and might be used to treat cold hypersensitivity and hyperalgesia in several neuropathic conditions, including complex regional pain syndrome and trigeminal neuralgia, peripheral nerve injury, and chemotherapy-induced neuropathy (Almeida et al, 2012;Gavva et al, 2012;Patel et al, 2014;Winchester et al, 2014). Moreover, TRPM8 has higher expression in prostate cancer tissue than in normal prostate tissue, and has also been detected in tumors of the breast, colon, lung, skin, and pancreas (Tsavaler et al, 2001;Yee et al, 2010;Okamoto et al, 2012).…”