TRPC3: A New Target for Therapeutic Strategies in Chronic Pain-DAG-mediated Activation of Non-selective Cation Currents and Chronic Pain (Mol Pain 2014;10:43).

Abstract

Chronic visceral pain is a typical condition associated with inflammation. The mechanism of visceral pain in chronic abdominal pain syndromes, such as irritable bowel syndrome and chronic pancreatitis, is poorly understood and its treatment has been largely empirical, with an outcome that is variable and frequently unsatisfactory. Human and experimental studies have indicated a critical role of neuronal mechanisms that result in peripheral and central sensitization.1–3 The nociceptive sensitization, literally meaning sensitization to noxious stimuli, begins with the primary afferent nociceptor, a nerve whose cell body lies in the dorsal root ganglia (DRG). DRG is located next to the spinal cord and has 2 branches: a long peripheral one terminating in the target tissue and a shorter central process that ends in the dorsal horn of the spinal cord. The peripheral process of these neurons senses tissue injury via a variety of receptors that respond to specific physical or chemical factors in the injured environment. In studying visceral pain, several visceral nociceptors have been identified as significant factors in inflammatory condition. For instance, A-type potassium channel is downregulated in chronic pancreatitis.2 Others, including transient receptor potential vanilloid 1,4 nerve growth factor,5 the protease activated receptor 2 (PAR2),6 and transforming growth factor beta1,7 are upregulated. In a further mechanism study on those nociceptors in thoracic/lumbar DRG, a prolonged intracellular calcium elevation is commonly associated with the neuronal hyper-excitability or hyper-sensitivity, contributing to nociception and chronic pain (hyperalgesia or allodynia). There are 2 distinct mechanisms proposed in modulating the intracellular calcium level when noxious stimuli activating the cognate membrane receptors at the surface of nociceptors.8 Store-operated calcium entry (SOCE) involves in activation of calcium channels by inositol 1,4,5-trisphosphate which is the key for calcium depletion from endoplasmic reticulum calcium stores; receptor-operated calcium entry (ROCE) involves in activation of calcium permeable channels directly by DAG.9,10 It remains unknown whether ROCE mechanism sensitizes the sensory neuron, however, SOCE component participates in calcium homeostasis and plays a significant role in chronic pain pathologies. Recently, Alkhani et al11 published “Contribution of TRPC3 to store-operated calcium entry and inflammatory transductions in primary nociceptors” in Molecular Pain. This study reveals a major contribution of transient receptor potential cation channels (TRPC) to neuronal calcium homeostasis in somatosensory pathways. These channels are non-selectively permeable to cations, with a selectivity of calcium over sodium variable among the different members. Here, TRPC engages in both SOCE and ROCE in control of calcium influx that triggers calcium-dependent pathways and peripheral sensitization. Therefore TRPC is functionally coupled to several inflammatory transductions, including UTP/P2Y2 and proteases/PAR2 signaling complexes. Logically, this unique dual contribution to SOCE and ROCE defines the calcium-permeable TRPC3 channel as a key regulator of calcium homeostasis in DRG neurons in normal or pathological pain conditions. Therefore, TRPC3 is a new target for therapeutic strategies in chronic pain.