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Review
. 2015 May 21;2(2):258-76.
doi: 10.1080/23328940.2015.1043042. eCollection 2015 Apr-Jun.

The involvement of TRPV1 in emesis and anti-emesis

John A Rudd  1 , Eugene Nalivaiko  2 , Norio Matsuki  3 , Christina Wan  4 , Paul Lr Andrews  5
Affiliations
Review

The involvement of TRPV1 in emesis and anti-emesis

John A Rudd et al. Temperature (Austin). .

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.

Keywords: 12-HPETE, 12-hydroperoxy-eicosatetraenoic acid; 5-HT, 5-hydroxytryptamine; 5-HT3, 5-hdroxytryptamine3; 8-OH-DPAT, (±)-8-Hydroxy-2-dipropylaminotetralin; AM404; AM404, N-arachidonoylaminophenol; AMT, anandamide membrane transporter; AP, area postrema; BBB, blood brain barrier; CB1, cannabinoid1; CGRP, calcitonin gene-related peptide; CINV, chemotherapy-induced nausea and vomiting; CP 99,994; CTA, conditioned taste aversion; CVO's, circumventricular organs; D2, dopamine2; DRG, dorsal root ganglia; FAAH, fatty acid amide hydrolase; H1, histamine1; LTB4, leukotriene B4; NADA, N-arachidonoyl-dopamine; NK1, neurokinin1; POAH, preoptic anterior hypothalamus; RTX; Suncus murinus; TRPV1; TRPV1, transient receptor potential vanilloid receptor1; anti-emetic; capsaicin; ferret; i.v., intravenous; nausea; olvanil; thermoregulation; vanilloid; vomiting.

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Figures

Figure 1.
Figure 1.
The latency (mean ± s.e.m, where available) of the emetic response to a variety of emetic stimuli in Suncus murinus. The TRPV1 ligands discussed in the text are highlighted in yellow. For references see: [1] Hu, D.L. et al., J Food Prot, 1999. 62: 1350–3.; [2] Ito, C. et al., Eur J Pharmacol, 1995. 285: 37–43.; [3] Chan, S.W. et al., Neuropharmacology, 2013. 70: 141–147.; [4] Mutoh, M. et al., Jpn J Pharmacol, 1992. 58: 321–4.; [5] Chen, Y. et al., Life Sci, 1997. 60: 253–61.; [6] Wan, C. et al., Unpublished observations, 2004.; [7] Yamahara, J. et al., J Ethnopharmacol, 1989. Twenty-seven: 353–5.; [8] Torii, Y. et al. J Radiat Res (Tokyo), 1993. 34: 164–70.; [9] Torii, Y. et al., Br J Pharmacol, 1994. 111: 431–4.; [10] Torii, Y. et al., Naunyn Schmiedebergs Arch Pharmacol, 1991. 344: 564–7.; [11] Cheng, F.H. et al., Eur J Pharmacol, 2005. 508: 231–8.; [12] Tashiro, N. et al., J Am Assoc Lab Anim Sci, 2007. 46: 81–5.; [13] Kan, K.K. et al., Eur J Pharmacol, 2003. 477: 247–51.; [14] Fujiwara-Sawada, M. et al., Pharmacometrics, 2000. 59: 39–46.; [15] Javid, F.A. et al., Eur J Pharmacol, 2013. 699: 48–54.; [16] Kan, K.K. et al. Eur J Pharmacol, 2003. 482: 297–304.; [17] Yamamoto, K. et al., Physiol Behav, 2004. 83: 151–6.; [18] Gardner, C. et al. Neuropharmacology, 1998. 37: 1643–4.; [19] Andrews, P.L.R. et al. Br J Pharmacol, 2000. 130: 1247–54.; [20] Rudd, J.A. et al. Eur J Pharmacol, 1999. 366: 243–52.; [21] Gardner, C.J. et al. Br J Pharmacol, 1995. 116: 3158–63.; [22] Ikegaya, Y. et al. Jpn J Pharmacol, 2002. 89: 324–6.; and [23] Smith, J.E. et al., Exp Physiol, 2002. 87: 563–74.
Figure 2.
Figure 2.
Diagram summarising potential brainstem sites at which resiniferatoxin (RTX ) given either subcutaneously (s.c.) or intracerebroventricularly (i.c.v.) in Suncus murinus can induce emesis. When given s.c. (1) RTX could access peripheral terminals of abdominal vagal afferents or the nodose ganglion (2) to cause activation of the brainstem nucleus tractus solitarius (NTS) via the release of substance P. The NTS could also be accessed by RTX from the circulation (3) as could the area postrema. The area postrema is the most likely site at which RTX given i.c.v. (4) acts but it is also possible that RTX could diffuse into the NTS via the area postrema where the blood-brain barrier is relatively permeable. At none of these locations are we able to distinguish between an action of RTX on TRPV1 receptors located on the cell bodies or presynaptically. Although it is likely that RTX induces substance P release at several sites in the dorsal brainstem it is known that substance P acting on NK1 receptors occupy a pivotal position in the emetic pathway at the point where the signals integrated in the NTS drive nausea and vomiting (5) so this may also be a likely site at which RTX could induce substance P release to induce emesis. It is speculated that the emetic effect of s.c. RTX is not seen in ferret or dog because the peak plasma concentration is lower resulting in a slower release of substance P so that the threshold (T) for induction of emesis at site 5 is not reached. This site (5) is also the most likely location at which RTX causes depletion of substance P (and possibly other transmitters) to have its broad spectrum anti-emetic effect observed in ferret, dog and Suncus murinus. See text for details and references.
Figure 3.
Figure 3.
A summary of the biological effects of resiniferatoxin (RTX) given subcutaneously (s.c.) in a range of species indicated by the silhouette. RTX may cause undesirable effects (red) including emesis, genesis of conditioned taste aversion (CTA), hypertension, stimulation of intense ano-genital grooming and hypothermia. However, RTX also has the desirable effect of being a broad-spectrum anti-emetic agent with the range of emetic stimuli affected shown on the right hand side (green). The primary aim of much of the research described in the review is to identify the mechanism of the anti-emetic effect and identify compounds capable of anti-emesis and devoid of the undesirable effects.Symbols:Suncus murinus: Dog: Ferret: Rat: Further details and references to published data are given in the text: CTA is from rat using a 2 bottle choice design with saccharin (Rudd et al. unpublished); Emesis and ano-genital grooming data is from Suncus murinus plotted (Rudd et al., unpublished; blood pressure and core temperature data is from conscious ferrets implanted with a radio-telemetery transmitter derived from data shown in Chu et al., 2010. Neuropharmacology 58, 383–91.
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