Zsa Zsa Weerts

A putative anti-inflammatory role for TRPM8 in IBS 105 5 Introduction Irritable bowel syndrome (IBS) is a disorder of gut–brain interaction characterized by chronic recurrent pain and altered bowel habits thought to arise from disturbances in the neuro-immune regulatory balance of afferent signal processing. 1 IBS is highly prevalent with an estimated prevalence in the general population of ~5%. 2 In addition, IBS has a profound negative impact on quality of life and carries a substantial socioeconomic burden. 3 Patients are diagnosed based on their symptoms using the Rome criteria. 4 Importantly, these symptoms occur in the absence of gross structural abnormalities. The sensory symptoms of pain are the most debilitating aspects to patients yet are the least responsive to pharmacological treatment, highlighting the lack of understanding of the mediators and mechanisms involved in pain sensing of the lower gastrointestinal tract. We recently demonstrated that peppermint oil 5 , a commonly used therapeutic in IBS, was able to improve pain outcomes. The beneficial effects of peppermint oil have also been confirmed in recent meta-analyses. 6,7 However, the mechanism of action remains somewhat obscure. Traditionally, peppermint oil is considered an anti-spasmodic due to the inhibition of calcium influx into the sarcolemma of the intestinal smooth muscle cells. On the other hand, the primary constituent of peppermint oil L-menthol, is also an agonist for the transient receptor potential melastatin 8 (TRPM8) channel. TRPM8 has an established role as an ion channel that responds to cold temperatures (<30°C), and the aforementioned menthol, a cyclic terpene alcohol found in mint leaves. 8 Expression of TRPM8 has been described in a distinct population of sensory nerves including trigeminal ganglia (TG), dorsal root ganglia (DRGs) and in epithelial cells of the prostate and bladder. 9 In the murine gastrointestinal tract, TRPM8 is expressed on colonic primary afferent neurons and activation of the channel with the agonist icilin inhibits chemo- and mechanosensory responses of pro-nociceptive TRP channels (TRPV1, TRPA1). 10 The activation of these pro-nociceptive channels also leads to the release of pro-inflammatory mediators from afferent nerve endings, resulting in a phenomenon collectively referred to as neurogenic inflammation. 11 Interestingly, in mouse models of colonic inflammation, TRPM8 knock-out mice have a more severe disease phenotype 12,13 and treatment with TRPM8 agonist icilin attenuates colonic inflammation. 14 Specifically, activation of TRPM8 expressed on calcitonin-gene related peptide (CGRP) containing sensory nerves reduces mucosal inflammation by inducing CGRP release, which then inhibits release of pro-inflammatory cytokines IL-6 and tumour necrosis factor (TNF)- α by CD11c+ dendritic cells. 13 Furthermore, murine macrophages expressing TRPM8 regulate pro- and anti-inflammatory mechanisms via