Positive allosteric modulation of TRPV1 as a novel analgesic mechanism

Abstract

Background: The prevalence of long-term opiate use in treating chronic non-cancer pain is increasing, and prescription opioid abuse and dependence are a major public health concern. To explore alternatives to opioid-based analgesia, the present study investigates a novel allosteric pharmacological approach operating through the cation channel TRPV1. This channel is highly expressed in subpopulations of primary afferent unmyelinated C-and lightly-myelinated Aδ-fibers that detect low and high rates of noxious heating, respectively, and it is also activated by vanilloid agonists and low pH. Sufficient doses of exogenous vanilloid agonists, such as capsaicin or resiniferatoxin, can inactivate/deactivate primary afferent endings due to calcium overload, and we hypothesized that positive allosteric modulation of agonist-activated TRPV1 could produce a selective, temporary inactivation of nociceptive nerve terminals in vivo. We previously identified MRS1477, a 1,4-dihydropyridine that potentiates vanilloid and pH activation of TRPV1 in vitro, but displays no detectable intrinsic agonist activity of its own. To study the in vivo effects of MRS1477, we injected the hind paws of rats with a non-deactivating dose of capsaicin, MRS1477, or the combination. An infrared diode laser was used to stimulate TRPV1-expressing nerve terminals and the latency and intensity of paw withdrawal responses were recorded. qRT-PCR and immunohistochemistry were performed on dorsal root ganglia to examine changes in gene expression and the cellular specificity of such changes following treatment.

Acute Capsaicin Supplementation Improved Resistance Exercise Performance Performed After a High-Intensity Intermittent Running in Resistance-Trained Men

“…There are 3 possible mechanisms by which TRVP1 agonists confer performance benefits. First, activation of TRVP1 leads to the inactivation or desensitization of primary nerve endings as a result of calcium overload, thereby resulting in an analgesic effect (9,16). Second, TRVP1 activation increases calcium release by sarcoplasmic reticulum (17,18), leading to higher interaction of actin-myosin filaments and potentially enhancing force production during fatiguing exercise (11,15,31).…”

“…In support of this hypothesis, an acute dose of 100 mg•kg 21 capsaicin was shown to increase force generation in mouse skeletal muscle during 6 minutes of repeating fatiguing isometric contractions (15), and 4 weeks of capsaicin supplementation increased relative forelimb grip strength in mice in a dose-dependent manner (11). Furthermore, the activation of TRPV1 receptor by capsaicin can generate analgesic effects by inactivating the primary affect nerve endings due calcium overload (16), which could increase the pain threshold and minimize the discomfort induced by fatiguing exercise decreasing the rating of perceived exertion (RPE). The results of these studies provide a mechanistic rationale by which capsaicin supplementation could improve performance and attenuate the interference effect of HIIE on resistance exercise.…”

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

“…Indeed, a new methodology was developed to screen for TRPV1 antagonists that do not inhibit capsaicin activation (Zicha et al, 2013). Added to this complexity are reports of allosteric TRPV1 modulators Lebovitz et al, 2012) and partial agonists/antagonists . The Amgen group postulated that hyperthermia is a function of proton activation (Lehto et al, 2008): Antagonists that do not interfere with the proton activation of TRPV1 are devoid of hyperthermia.…”

Current and emerging therapies in premature ejaculation: Where we are coming from, where we are going

“…The compound has the ability to activate primary afferent sensory neurons by increasing calcium permeability. This influx is initially met with a significant burning sensation followed by analgesia as a result of neuronal death caused by calcium overload . Resiniferatoxin has been shown to improve IELT in patients with PE .…”