The involvement of TRPV1 in emesis and anti-emesis

Abstract

Diverse transmitter systems (e.g. acetylcholine, dopamine, endocannabinoids, endorphins, glutamate, histamine, 5-hydroxytryptamine, substance P) have been implicated in the pathways by which nausea and vomiting are induced and are targets for anti-emetic drugs (e.g. 5-hydroxytryptamine3 and tachykinin NK1 antagonists). The involvement of TRPV1 in emesis was discovered in the early 1990s and may have been overlooked previously as TRPV1 pharmacology was studied in rodents (mice, rats) lacking an emetic reflex. Acute subcutaneous administration of resiniferatoxin in the ferret, dog and Suncus murinus revealed that it had “broad–spectrum” anti-emetic effects against stimuli acting via both central (vestibular system, area postrema) and peripheral (abdominal vagal afferents) inputs. One of several hypotheses discussed here is that the anti-emetic effect is due to acute depletion of substance P (or another peptide) at a critical site (e.g. nucleus tractus solitarius) in the central emetic pathway. Studies in Suncus murinus revealed a potential for a long lasting (one month) effect against the chemotherapeutic agent cisplatin. Subsequent studies using telemetry in the conscious ferret compared the anti-emetic, hypothermic and hypertensive effects of resiniferatoxin (pungent) and olvanil (non-pungent) and showed that the anti-emetic effect was present (but reduced) with olvanil which although inducing hypothermia it did not have the marked hypertensive effects of resiniferatoxin. The review concludes by discussing general insights into emetic pathways and their pharmacology revealed by these relatively overlooked studies with TRPV1 activators (pungent an non-pungent; high and low lipophilicity) and antagonists and the potential clinical utility of agents targeted at the TRPV1 system.

Successful Treatment of Cannabinoid Hyperemesis Syndrome with Topical Capsaicin

“…Activation of TRPV1 has potent anti-emetic effects, which may be mediated by depletion of substance P from neural circuits traveling to the nucleus tractus solitarius. 9 , 10 …”

Pathophysiological and neurochemical mechanisms of postoperative nausea and vomiting

“…For example, at low doses morphine and other opioid receptor agonists produce emesis but at higher doses emesis is inhibited – a bell-shaped dose response curve (Barnes et al, 1991; Bhandari et al, 1992; Thompson et al, 1992). Based on receptor affinity, morphine and fentanyl are likely to exert their emetic effects via μ opioid receptors but actions at kappa and delta receptor subtypes cannot be ruled out (Rudd and Naylor, 1995). …”

Cannabinoid Hyperemesis

“…Endocanna­binoids (anandamide) along with exogenous cannabinoids (cannabidiol [CBD], cannabidivarin) are TRPV1 agonists [23, 24]. To complicate the picture, TRPV1 agonism appears to be proemetic when ligand concentration is low, but antiemetic when ligand concentration is high [23, 24]. Extreme stimulation can desensitize TRPV1 and be proemetic [25].…”

“…There is a high density of TRPV1 receptors in the area postrema known as the “trigger zone” for emesis [22]. Endocanna­binoids (anandamide) along with exogenous cannabinoids (cannabidiol [CBD], cannabidivarin) are TRPV1 agonists [23, 24]. To complicate the picture, TRPV1 agonism appears to be proemetic when ligand concentration is low, but antiemetic when ligand concentration is high [23, 24].…”