Supraspinal-selective TRPV1 desensitization induced by intracerebroventricular treatment with resiniferatoxin

Abstract

The transient receptor potential vanilloid type 1 (TRPV1) is a thermosensitive cation channel that triggers heat pain in the periphery. Long-term desensitization of TRPV1, which can be induced by excess amounts of agonists, has been a method for investigating the physiological relevance of TRPV1-containing neuronal circuits, and desensitization induced by various routes of administration, including systemic, intrathecal and intraganglionic, has been demonstrated in rodents. In the present study, we examined the effect of intracerebroventricular (i.c.v.) treatment with an ultrapotent TRPV1 agonist, resiniferatoxin (RTX), on nociception and the analgesic effect of acetaminophen, which is known to mediate the activation of central TRPV1. I.c.v. administration of RTX a week before the test did not affect the licking/biting response to intraplantar injection of RTX (RTX test), suggesting that such i.c.v. treatment spares the function of TRPV1 at the hindpaw. Mice that had been i.c.v.-administered RTX also exhibited normal nociceptive responses in the formalin test and the tail pressure test, but acetaminophen failed to induce analgesia in those mice in any of the tests. These results suggest that i.c.v. administration of RTX leads to brain-selective TRPV1 desensitization in mice.

Paracetamol is a centrally acting analgesic using mechanisms located in the periaqueductal grey

“…Recent work on the mechanism of action of paracetamol suggests that it is metabolised by the liver into p ‐aminophenol, which is then conjugated with arachidonic acid, especially in the brain, to form AM404 ( N ‐(4‐hydroxyphenyl)‐5 Z ,8 Z ,11 Z ,14 Z ‐eicosatetraenamide) through the activity of the enzyme, fatty acid amide hydrolase (FAAH) (Dalmann, Daulhac, Antri, Eschalier, & Mallet, ; Högestätt et al, ; Mallet et al, ). In the brain, AM404 may then promote activation of the central endocannabinoid system through action at both TRPV1 channels and cannabinoid CB 1 receptors (Ottani, Leone, Sandrini, Ferrari, & Bertolini, ; Mallet et al, ; Mallet et al, ; Barrière et al, ; Kerckhove et al, ; Fukushima, Mamada, Iimura, & Ono, ; Klinger‐Gratz et al, ). However, the precise central mechanisms promoting its analgesic effects are still unknown.…”

α1‐Blocker inhibits non‐voiding contractions and decreases the level of intravesical prostaglandin E2 in rats with partial bladder outlet obstruction

“…Systemic RTX induces desensitization of TRPV1 1–40 days after RTX injection . Thus, urinary TRPV1 was probably functionally downregulated in the present study, and afferent nerve activity from the urothelium was probably attenuated.…”

A Network Medicine Approach to Drug Repurposing for Chronic Pancreatitis

“…Capsaicin has been shown to activate and sensitise pancreatic nociceptors and increase neuropathic pain [13]. Conversely, excessive TRPV1 agonism is known to lead to cytotoxic calcium overload and cell death of TRPV1-positive neurons [14]. Resiniferatoxin (RTX) (a naturally-occurring ultrapotent capsacain analogue and TRPV1 agonist) is currently in multiple clinical trials for urinary bladder hyper-reflexia and chronic pain conditions such as osteoarthritis.…”

“…Oxidative, electrophilic, ER, and inflammation stress are widely regarded to contribute to the pathogenesis of CP [13]. Micronutrient therapy has been suggested to inhibit various etiological stresses [20].…”