Current insights and therapeutic strategies for targeting TRPV1 in neuropathic pain management.

Neuropathic pain, a common symptom of several disorders, exerts a substantial socioeconomic burden worldwide. Transient receptor potential vanilloid 1 (TRPV1), a non-selective cation channel predominantly ex-pressed in nociceptive neurons, plays a pivotal role in nociception, by detecting various endogenous and exogenous stimuli, including heat, pro-inflammatory mediators, and physical stressors. Dysregulation of TRPV1 signaling further contributes to the pathophysiology of neuropathic pain. Therefore, targeting TRPV1 is a promising strategy for developing novel analgesics with improved efficacy and safety profiles. Several pharmacological approaches to modulate TRPV1 activity, including agonists, antagonists, and biological TRPV1 RNA interference (RNAi, small interfering RNA [siRNA]) have been explored. Despite preclinical success, the clinical translation of TRPV1-targeted therapies has encountered challenges, including hyperthermia, hypothermia, pungency, and desensitization. Nevertheless, ongoing research efforts aim to refine TRPV1-targeted interventions through structural modifications, development of selective modulators, and discovery of natural, peptide-based drug candidates. Herein, we provide guidance for researchers and clinicians involved in the development of new interventions specifically targeting TRPV1 by reviewing the existing literature and highlighting current research activities. This study further discusses potential future research endeavors for enhancing the efficacy, safety, and tolerability of TRPV1 candidates, and thereby facilitates the translation of these discoveries into effective clinical interventions to alleviate neuropathic pain disorders.

The Effect of Intermittent Pneumatic Compression on Hemodynamics and Regional Cerebral Oxygen Saturation in Laparoscopic Bariatric Surgery with Mild Hypercapnia in the Steep Reverse Trendelenburg Position.

Obesity negatively affects hemodynamics and cerebral physiology. We investigated the effect of the utilization of an intermittent pneumatic compression (IPC) device on hemodynamics and cerebral physiology in patients undergoing laparoscopic bariatric surgery under general anesthesia with lung-protective ventilation. Sixty-four patients (body mass index > 30 kg/m2) were randomly assigned to groups that received an IPC device (IPC group, n = 32) and did not (control group, n = 32). The mean arterial pressure (MAP), heart rate (HR), need for vasopressors, cerebral oxygen saturation (rSO2), and cerebral desaturation events were recorded. The incidence of intraoperative hypotension was not significantly different between groups (p = 0.153). Changes in MAP and HR over time were similar between groups (p = 0.196 and p = 0.705, respectively). The incidence of intraoperative cerebral desaturation was not significantly different between groups (p = 0.488). Changes in rSO2 over time were similar between the two groups (p = 0.190) during pneumoperitoneum. Applying IPC to patients with obesity in the steep reverse Trendelenburg position may not improve hemodynamic parameters, vasopressor requirements, or rSO2 values during pneumoperitoneum under lung-protective ventilation. During laparoscopic bariatric surgery, IPC alone has limitations in improving hemodynamics and cerebral physiology.

GLP-1 and Its Derived Peptides Mediate Pain Relief Through Direct TRPV1 Inhibition Without Affecting Thermoregulation.

Hormonal regulation during food ingestion and its association with pain prompted the investigation of the impact of glucagon-like peptide-1 (GLP-1) on the transient receptor potential vanilloid 1 (TRPV1). Both endogenous and synthetic GLP-1 and an antagonist of GLP-1, exendin 9-39, reduced heat sensitivity in naïve mice. GLP-1-derived peptides (liraglutide, exendin-4, and exendin 9-39) effectively inhibited capsaicin (CAP)-induced currents and calcium responses in cultured sensory neurons and TRPV1-expressing cell lines. Notably, the exendin 9-39 alleviated CAP-induced acute pain, as well as chronic pain induced by complete Freund's adjuvant (CFA) and spared nerve injury (SNI) in mice, without causing hyperthermia associated with other TRPV1 inhibitors. Electrophysiological analyses revealed that exendin 9-39 binds to the extracellular side of TRPV1, functioning as a noncompetitive inhibitor of CAP. Exendin 9-39 did not affect proton-induced TRPV1 activation, suggesting its selective antagonism. Among exendin 9-39 fragments, exendin 20-29 specifically binds to TRPV1, alleviating pain in both acute and chronic pain models without interfering with GLP-1R function. Our study revealed a novel role for GLP-1 and its derivatives in pain relief, proposing exendin 20-29 as a promising therapeutic candidate.