Neurotrophins, endocannabinoids and thermo‐transient receptor potential: a threesome in pain signalling

Abstract

Because of the social and economic costs of chronic pain, there is a growing interest in unveiling the cellular and molecular mechanisms underlying it with the aim of developing more effective medications. Pain signalling is a multicomponent process that involves the peripheral and central nervous systems. At the periphery, nociceptor sensitisation by pro-inflammatory mediators is a primary step in pain transduction. Although pain is multifactorial at cellular and molecular levels, it is widely accepted that neurotrophin (TrkA, p75NTR, Ret and GFRs), cannabinoid (CB1 and CB2), and thermo-transient receptor potential (TRPs; TRPV1, TRPA1 and TRPM8) receptors play a pivotal role. They form a threesome for which endocannabinoids appear to be a first line of defence against pain, while neurotrophins and thermoTRPs are the major generators of painful signals. However, endocannabinoids may exhibit nociceptive activity while some neurotrophins may display anti-nociception. Accordingly, a clear-cut knowledge of the modulation and context-dependent function of these signalling cascades, along with the molecular and dynamic details of their crosstalk, is critical for understanding and controlling pain transduction. Here, the recent progress in this fascinating topic, as well as the tantalizing questions that remain unanswered, will be discussed. Furthermore, we will underline the need for using a systems biology approach (referred to as systems pain) to uncover the dynamics and interplay of these intricate signalling cascades, taking into consideration the molecular complexity and cellular heterogeneity of nociceptor populations. Nonetheless, the available information confirms that pharmacological modulation of this signalling triad is a highly valuable therapeutic strategy for effectively treating pain syndromes.

Activation of cannabinoid CB1 receptor contributes to suppression of spinal nociceptive transmission and inhibition of mechanical hypersensitivity by Aβ-fiber stimulation

“…20,23,26,49,54 The spinal endocannabinoid system generally helps to maintain the balance of neuronal excitability and certainly has a therapeutic potential for pain treatment. 16,31,65 Our study suggests that CB1 receptors may be another useful target for developing new treatment strategies, as CB1 receptor agonists or endocannabinoid degradation inhibitors might increase the efficacy of SCS and prolong pain inhibition.…”

Inflammatory and neuropathic cold allodynia are selectively mediated by the neurotrophic factor receptor GFRα3

“…However, specific changes in TRPV1 channel activity have not been reported, and the preponderance of data suggests that artemin-induced heat hyperalgesia is caused by increased TRPV1 expression (27,28,46,47). Moreover, unlike the established TRPM8 dependence of arteminand NGF-evoked cold allodynia (8) or the necessity of TRPV1 for NGF-induced heat hyperalgesia (36), the molecule determinants of GFL-evoked alterations in nociception in vivo are unknown (48).…”

Blocking TRPA1 and TNF-α Signal Improves Bortezomib-Induced Neuropathic Pain

“…Thus, we speculated that the effects of blocking TNF-α would improve dysregulation of calcium homeostasis in attenuating neuropathic pain. In addition, increases in neurotrophins (such as nerve growth factor) can amplify pain response and upregulation of TRPA1 expression and increases of TRPA1 activity are partly involved in the effects of neurotrophins [39,40]. Thus, enhancement of TRPA1 observed in this study is likely linked to dysregulation of neurotrophins in BTZ-induced neuropathy [36].…”