Involvement of TRPM2 in a wide range of inflammatory and neuropathic pain mouse models

Abstract

Recent evidence suggests a role of transient receptor potential melastatin 2 (TRPM2) in immune and inflammatory responses. We previously reported that TRPM2 deficiency attenuated inflammatory and neuropathic pain in some pain mouse models, including formalin- or carrageenan-induced inflammatory pain, and peripheral nerve injury-induced neuropathic pain models, while it had no effect on the basal mechanical and thermal nociceptive sensitivities. In this study, we further explored the involvement of TRPM2 in various pain models using TRPM2-knockout mice. There were no differences in the chemonociceptive behaviors evoked by intraplantar injection of capsaicin or hydrogen peroxide between wildtype and TRPM2-knockout mice, while acetic acid-induced writhing behavior was significantly attenuated in TRPM2-knockout mice. In the postoperative incisional pain model, no difference in mechanical allodynia was observed between the two genotypes. By contrast, mechanical allodynia in the monosodium iodoacetate-induced osteoarthritis pain model and the experimental autoimmune encephalomyelitis model were significantly attenuated in TRPM2-knockout mice. Furthermore, mechanical allodynia in paclitaxel-induced peripheral neuropathy and streptozotocin-induced painful diabetic neuropathy models were significantly attenuated in TRPM2-knockout mice. Taken together, these results suggest that TRPM2 plays roles in a wide range of pathological pain models based on peripheral and central neuroinflammation, rather than physiological nociceptive pain.

Muscle Reactive Oxygen Species (ROS) Contribute to Post-Incisional Guarding via the TRPA1 Receptor

“…Intraplantar injection of H 2 O 2 caused brief nociceptive pain [19], but specific subcutaneous versus deep tissue injections were not studied and would be difficult in such small spaces like the hind paw. In other previous studies, after intraplantar injection of H 2 O 2 , nociceptive behavior was short-lasting (< 5 min), which is consistent with our finding after subcutaneous injection over the gastrocnemius [30, 33, 34]. In humans, cutaneous wounds are frequently flushed or rinsed with much higher concentrations of H 2 O 2 (880 mM concentration of commercially-available 3% H 2 O 2 ).…”

Physiological and Pathophysiological Roles of Transient Receptor Potential Channels in Microglia-Related CNS Inflammatory Diseases

“…Microglial/Macrophagic TRPM2 Channels in Neuropathic Pain TRPM2 is thought to be involved in a range of pathological pain states, including neuropathic pain. 31,36,37) Evidence suggests that peripheral and spinal neuroinflammation mediated by the interaction between nociceptive neurons and immune/glial cells plays a pivotal role in neuropathic pain. 38) After peripheral nerve injury, pro-nociceptive inflammatory mediators, such as pro-inflammatory cytokines, chemokines, and excess ROS produced by peripheral tissues and the spinal cord, can lead to peripheral and central sensitization of nociceptive neurons.…”

“…36) Consequently, TRPM2 is involved in a wide range of pathological pain states induced by peripheral and spinal neuroinflammation-such as inflammatory pain, osteoarthritic pain, neuropathic pain induced by peripheral nerve injury, chemotherapy-induced peripheral neuropathy, and painful diabetic neuropathy-rather than in physiological nociceptive pain. 37) …”

Nitroxidative Signaling Mechanisms in Pathological Pain

“…TRPM2 also activates ERK MAPK and induces nuclear translocation of NFκB, resulting in production of proinflammatory cytokines and chemokines [76,77,81,83,84]. Consequently, pharmacological and genetic studies have demonstrated that TRPM2 contributes to inflammatory and neuropathic nociceptive hypersensitivity [77–79,82,85]. …”