Neuron (Cambridge, Mass.), 2024-06, Vol.112 (11), p.1815-1831.e4
2024
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- Autor(en) / Beteiligte
- Titel
- TRPV1 analgesics disturb core body temperature via a biased allosteric mechanism involving conformations distinct from that for nociception
- Ist Teil von
- Neuron (Cambridge, Mass.), 2024-06, Vol.112 (11), p.1815-1831.e4
- Ort / Verlag
- United States: Elsevier Inc
- Erscheinungsjahr
- 2024
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Efforts on developing transient receptor potential vanilloid 1 (TRPV1) drugs for pain management have been hampered by deleterious hypo- or hyperthermia caused by TRPV1 agonists/antagonists. Here, we compared the effects of four antagonists on TRPV1 polymodal gating and core body temperature (CBT) in Trpv1+/+, Trpv1−/−, and Trpv1T634A/T634A. Neither the effect on proton gating nor drug administration route, hair coverage, CBT rhythmic fluctuations, or inflammation had any influence on the differential actions of TRPV1 drugs on CBT. We identified the S4-S5 linker region exposed to the vanilloid pocket of TRPV1 to be critical for hyperthermia associated with certain TRPV1 antagonists. PSFL2874, a TRPV1 antagonist we discovered, is effective against inflammatory pain but devoid of binding to the S4-S5 linker and inducing CBT changes. These findings implicate that biased allosteric mechanisms exist for TRPV1 coupling to nociception and CBT regulation, opening avenues for the development of non-opioid analgesics without affecting CBT. [Display omitted] •TRPV1 analgesics’ impact on proton gating does not contribute to CBT disturbance•Biased allosteric mechanisms of TRPV1 are coupled to nociception and CBT regulation•The S4-S5 linker’s allostery is pivotal for hyperthermia in TRPV1 analgesics•Biased allosterism of TRPV1 facilitates the development of non-opioid analgesics Development of analgesics targeting TRPV1 receptors has been hampered by undesirable hypo- or hyperthermic effects induced by TRPV1 agonists/antagonists. Huang et al. suggest that biased allosteric mechanisms exist for TRPV1 coupling to nociception and CBT regulation, which may be selectively targeted for developing non-opioid analgesics without the confounding CBT alterations.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0896-6273, 1097-4199eISSN: 1097-4199DOI: 10.1016/j.neuron.2024.02.016Titel-ID: cdi_proquest_miscellaneous_2958293808
- Format
- –
- Schlagworte
- Allosteric Regulation - drug effects, Analgesics - pharmacology, Animals, biased allosteric mechanism, Body Temperature - drug effects, core body temperature, Humans, hyperthermia, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, nociception, Nociception - drug effects, Nociception - physiology, Pain - drug therapy, Pain - metabolism, S4-S5 linker domain, TRP-box domain, TRPV Cation Channels - genetics, TRPV Cation Channels - metabolism, TRPV1 analgesics