TRPV1 ligands with hyperthermic, hypothermic and no temperature effects in rats

Gomtsyan, Arthur; McDonald, Heath A.; Schmidt, Robert George; Daanen, Jerome F.; Voight, Eric A.; Segreti, Jason A.; Puttfarcken, Pamela S.; Reilly, Regina M.; Kort, Michael E.; Dart, Michael J.; Kym, Philip R.

doi:10.1080/23328940.2015.1046013

Cited by 25 publications

(19 citation statements)

References 28 publications

(23 reference statements)

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“…Recent studies on TRPV1 antagonists have highlighted the importance of TRPV1 expressing peripheral sensory nerves for temperature regulation. Stimulation of TRPV1 with systemic capsaicin treatment leads to hypothermia 9 38 , while administration of many (but not all) TRPV1 antagonists causes hyperthermia 12 40 41 42 . Functional ablation of these peripheral sensory neurons by prior administration of the ultrapotent TRPV1 agonist RTX results in a loss of TRPV1 mediated temperature changes 40 .…”

Section: Discussionmentioning

confidence: 99%

TRPA1 mediates the hypothermic action of acetaminophen

Gentry

Andersson

Bevan

2015

Sci Rep

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Acetaminophen (APAP) is an effective antipyretic and one of the most commonly used analgesic drugs. Unlike antipyretic non-steroidal anti-inflammatory drugs, APAP elicits hypothermia in addition to its antipyretic effect. Here we have examined the mechanisms responsible for the hypothermic activity of APAP. Subcutaneous, but not intrathecal, administration of APAP elicited a dose dependent decrease in body temperature in wildtype mice. Hypothermia was abolished in mice pre-treated with resiniferatoxin to destroy or defunctionalize peripheral TRPV1-expressing terminals, but resistant to inhibition of cyclo-oxygenases. The hypothermic activity was independent of TRPV1 since APAP evoked hypothermia was identical in wildtype and Trpv1−/− mice, and not reduced by administration of a maximally effective dose of a TRPV1 antagonist. In contrast, a TRPA1 antagonist inhibited APAP induced hypothermia and APAP was without effect on body temperature in Trpa1−/− mice. In a model of yeast induced pyrexia, administration of APAP evoked a marked hypothermia in wildtype and Trpv1−/− mice, but only restored normal body temperature in Trpa1−/− and Trpa1−/−/Trpv1−/− mice. We conclude that TRPA1 mediates APAP evoked hypothermia.

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Section: Discussionmentioning

confidence: 99%

TRPA1 mediates the hypothermic action of acetaminophen

Gentry

Andersson

Bevan

2015

Sci Rep

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“…The list of hypothermia‐inducing compounds includes several small‐molecule antagonists, viz., 5′‐iodo‐resiniferatoxin (5′‐I‐RTX), Amgen's AMG7905 and AMG8562, Abbott Laboratories’ A‐425619, AbbVie's Compound 3 and Schwarz Pharma's JYL1421, as well as at least 1 polypeptide antagonist, APHC3 . In agreement with the fact that TRPV1 agonists also cause hypothermia, several hypothermia‐causing TRPV1 antagonists, viz., 5′‐I‐RTX and Compound 3, were found to be partial agonists, whereas the partial antagonist APHC3 was found to potentiate the effects of low concentrations of capsaicin . However, several other hypothermia‐inducing TRPV1 antagonists, viz., A‐425619, AMG7905 and AMG8562 and JYL1421, showed no TRPV1 agonistic or capsaicin‐potentiating activity.…”

Section: Introductionmentioning

confidence: 55%

“…In fact, several authors hypothesized that hypothermia is not an on‐target effect . By the same token, there are reports showing that selective TRPV1 antagonists of different chemotypes cause hypothermia, which is suggestive of an on‐target nature of the hypothermic effect of TRPV1 antagonists. In this study, we show definitively that the hypothermic effects of A‐1165901 and AMG7905 occur only in the presence of TRPV1 channels.…”

Section: Discussionmentioning

confidence: 99%

“…Obtaining in‐protein crystal structures of thermally neutral, hyper‐ and hypothermic antagonists of the same chemotype (eg chromanyl ureas reported by Gomtsyan et al) would be required to propel highly targeted, structure‐driven design. Given that modern techniques produce sufficiently accurate TRPV1 structures to resolve side‐chain conformations in various environments and that the accurate structural information for TRPV1 in complex with various agonists and antagonists is already available (see, eg ref.…”

Section: Discussionmentioning

confidence: 99%

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TRPV1 antagonists that cause hypothermia, instead of hyperthermia, in rodents: Compounds’ pharmacological profiles, in vivo targets, thermoeffectors recruited and implications for drug development

et al. 2018

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AimThermoregulatory side effects hinder the development of transient receptor potential vanilloid‐1 (TRPV1) antagonists as new painkillers. While many antagonists cause hyperthermia, a well‐studied effect, some cause hypothermia. The mechanisms of this hypothermia are unknown and were studied herein.MethodsTwo hypothermia‐inducing TRPV1 antagonists, the newly synthesized A‐1165901 and the known AMG7905, were used in physiological experiments in rats and mice. Their pharmacological profiles against rat TRPV1 were studied in vitro.ResultsAdministered peripherally, A‐1165901 caused hypothermia in rats by either triggering tail‐skin vasodilation (at thermoneutrality) or inhibiting thermogenesis (in the cold). A‐1165901‐induced hypothermia did not occur in rats with desensitized (by an intraperitoneal dose of the TRPV1 agonist resiniferatoxin) sensory abdominal nerves. The hypothermic responses to A‐1165901 and AMG7905 (administered intragastrically or intraperitoneally) were absent in Trpv1 −/− mice, even though both compounds evoked pronounced hypothermia in Trpv1 +/+ mice. In vitro, both A‐1165901 and AMG7905 potently potentiated TRPV1 activation by protons, while potently blocking channel activation by capsaicin.Conclusion TRPV1 antagonists cause hypothermia by an on‐target action: on TRPV1 channels on abdominal sensory nerves. These channels are tonically activated by protons and drive the reflectory inhibition of thermogenesis and tail‐skin vasoconstriction. Those TRPV1 antagonists that cause hypothermia further inhibit these cold defences, thus decreasing body temperature.SignificanceTRPV1 antagonists (of capsaicin activation) are highly unusual in that they can cause both hyper‐ and hypothermia by modulating the same mechanism. For drug development, this means that both side effects can be dealt with simultaneously, by minimizing these compounds’ interference with TRPV1 activation by protons.

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“…Além das células neuronais, o TRPV1 é um canal catiónico não seletivo presente no músculo liso e epitélio do trato respiratório e na membrana plasmática dos neurônios sensoriais que inervam as vias aéreas superiores e inferiores 24 . O TRPV1 pode ser ativado por uma gama diversificada de ligantes químicos endógenos e exógenos, compostos vanilóides como a capsaicina, metabolitos de ácido araquidônico endógeno, pH baixo e temperaturas acima de 43°C [25][26][27][28][29][30][31][32][33] . Nesse sentido, estudos constataram que os receptores TRPV1 são superexpressados em pacientes com tosse crônica 34 .…”

Section: Fisiopatologiaunclassified

Aspectos fisiopatológicos do reflexo da tosse: uma revisão de literatura

Rodrigues

Galvão

2017

Rev. Med. (São Paulo)

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RESUMO:A tosse é um reflexo de defesa da via aérea em condições fisiológicas. Entretanto, ela compõe o quadro clínico de diversas doenças pulmonares, cardíacas e gastrintestinais. A persistência desse sintoma afeta a qualidade de vida do paciente e acomete 3 a 40% da população geral. Embora possua uma prevalência alta, a fisiopatologia desse sintoma ainda não é bem esclarecida. Nesse sentido, anualmente, são publicados novos achados sobre a fisiopatologia desse sintoma. Assim, o objetivo desse trabalho é realizar uma revisão de literatura sobre a fisiopatologia da tosse. Essa revisão utilizou quarenta publicações presentes nas seguintes bases de dados: Scholar Google, SciELO, Pubmed Central® (PMC), National Center for Biotechnology Information (NCBI) e Medline. A fisiopatologia da tosse está intimamente ligada à estimulação química das fibras-C e à ativação por estímulos mecânicos dos receptores de adaptação rápida (RARs) e dos receptores de estiramento de adaptação lenta (SARs). O conhecimento desses mecanismos fisiopatológicos é importante para o manejo clínico de pacientes com esse sintoma e contribui para o entendimento do mecanismo de ação de antitussígenos que agem sobre esses receptores.Descritores: Tosse/fisiopatologia; Tosse/diagnóstico; Reflexo; Antitussígenos. ABSTRACT:Cough is a reflex of airway defense under physiological conditions. However, it composes the clinical condition of several pulmonary, cardiac and gastrointestinal deseases. The persistence of the symptom affects the welfare of the patient and affects 3 to 40% of the general population. Although it has an important prevalence, the pathophysiology of the symptom is still not clear. In this sense, new symptom findings are published annually. Thus, the objective of the study is to perform a review of the pathophysiology of cough. This review used forty recent publications in the following databases: Scholar Google, SciELO, Pubmed Central® (PMC), National Center for Biotechnology Information (NCBI) and Medline. The pathophysiology of cough is closely linked to the chemical stimulation of C-fibers and to activation by mechanical stimuli of the rapid adaptation receptors (RARs) and the slow adaptating stretch receptors (SARs). The knowledge of these pathophysiological mechanisms is important for the clinical management of patients with this symptom and contributes to the understanding of the mechanism of action of antitussives that act on these receptors.

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TRPV1 ligands with hyperthermic, hypothermic and no temperature effects in rats

Cited by 25 publications

References 28 publications

TRPA1 mediates the hypothermic action of acetaminophen

TRPA1 mediates the hypothermic action of acetaminophen

TRPV1 antagonists that cause hypothermia, instead of hyperthermia, in rodents: Compounds’ pharmacological profiles, in vivo targets, thermoeffectors recruited and implications for drug development

Aspectos fisiopatológicos do reflexo da tosse: uma revisão de literatura

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