The dual role of TRPV1 in peripheral neuropathic pain: pain switches caused by its sensitization or desensitization

Abstract

The transient receptor potential vanilloid 1 (TRPV1) channel plays a dual role in peripheral neuropathic pain (NeuP) by acting as a "pain switch" through its sensitization and desensitization. Hyperalgesia, commonly resulting from tissue injury or inflammation, involves the sensitization of TRPV1 channels, which modulates sensory transmission from primary afferent nociceptors to spinal dorsal horn neurons. In chemotherapy-induced peripheral neuropathy (CIPN), TRPV1 is implicated in neuropathic pain mechanisms due to its interaction with ion channels, neurotransmitter signaling, and oxidative stress. Sensitization of TRPV1 in dorsal root ganglion neurons contributes to CIPN development, and inhibition of TRPV1 channels can reduce chemotherapy-induced mechanical hypersensitivity. In diabetic peripheral neuropathy (DPN), TRPV1 is involved in pain modulation through pathways including reactive oxygen species and cytokine production. TRPV1's interaction with TRPA1 channels further influences chronic pain onset and progression. Therapeutically, capsaicin, a TRPV1 agonist, can induce analgesia through receptor desensitization, while TRPV1 antagonists and siRNA targeting TRPV1 show promise in preclinical studies. Cannabinoid modulation of TRPV1 provides another potential pathway for alleviating neuropathic pain. This review summarizes recent preclinical research on TRPV1 in association with peripheral NeuP.

Keywords: TRPV1; desensitization; molecular mechanisms; peripheral neuropathic pain; sensitization.

Figure 1

Structural and functional overview of TRPV1 activation and desensitization. TRPV1 is composed of three parts: intracellular N and C termini, six transmembrane domains (S1–S6), and a pore loop region formed between S5 and S6. It can be activated by various physical and chemical stimuli, such as noxious heat (>43°C), divalent cations, low pH, inflammatory mediators, and animal toxins. Activation of this channel leads to significant influxes of Ca²⁺ and Na⁺, causing neuronal depolarization and action potential discharge. Prolonged stimulation enhances TRPV1 activation, reducing neuronal excitability and resulting in near or complete insensitivity to subsequent stimuli, a phenomenon known as specific desensitization. Additionally, elevated intracellular calcium levels can activate the calcium-dependent protease calpain, which degrades cytoskeletal components within axons, leading to axonal structural damage and functional loss.