Peritoneal delivery of capsinoids, nonpungent TRPV1 agonists, induces mild hypothermia in conscious mice through TRPV1 activation of visceral vagal afferents

Authors: ANDERSOHN, ALEXANDER - University Of Texas; WU, TING - University Of Texas; DOAN, ANDREA - University Of Texas; Cantrell, Charles; Jarret, Robert; MARRELLI, SEAN - University Of Texas

Submitted to: Scientific Reports
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/21/2025
Publication Date: 10/27/2025
Citation: Andersohn, A., Wu, T., Doan, A., Cantrell, C.L., Jarret, R.L., Marrelli, S.P. 2025. Peritoneal delivery of capsinoids, nonpungent TRPV1 agonists, induces mild hypothermia in conscious mice through TRPV1 activation of visceral vagal afferents. Scientific Reports. 15:37478. https://doi.org/10.1038/s41598-025-21388-6.
DOI: https://doi.org/10.1038/s41598-025-21388-6

Interpretive Summary: Stroke is the leading cause of long-term disability and the fifth leading cause of death in the United States1. Despite major advances in the treatment of ischemic stroke (i.e. thrombolysis and thrombectomy), a large number of patients are still left with significant brain injury and lasting neurological deficits. Thus, additional treatment options are still needed for patients with ischemic stroke. Therapeutic hypothermia (TH) has been shown to be effective in other conditions that lead to brain hypoxia, including cardiac arrest and neonatal hypoxic-ischemic encephalopathy (nHIE). Indeed, the use of TH for the treatment of cardiac arrest and nHIE has been standard clinical care for over a decade. In experimental stroke models, TH has been repeatedly shown to provide significant neuroprotection and improved functional outcome. Unfortunately, efforts to translate this benefit to human stroke patients have faced multiple challenges, largely related to the counterproductive activation of robust cold defense mechanisms. The purpose of this study was to determine the efficacy of capsinoids to induce a therapeutically relevant hypothermia in conscious mice. Capsinoids are non-pungent TRPV1 agonists that offer particular translational promise due to their reduced potential for activating TRPV1-linked pain pathways. Herein, we demonstrate that capsinoids, when delivered to the peritoneal cavity, can provide a TRPV1-mediated induction of mild hypothermia in conscious mice that may be suitable for application to post-stroke neuroprotection.

Technical Abstract: Despite advancements in ischemic stroke treatment, significant brain injury and disability remain common, necessitating additional therapies. Therapeutic hypothermia (TH) has shown benefits in other ischemic injuries but faces challenges in clinical stroke patients due to difficulty in achieving and maintaining hypothermic temperatures and activation of cold defense mechanisms, which require heavy paralytics or sedatives to counteract, preventing their use in conscious patients. Pharmacological activation of TRPV1 channels with agonists induces a mild hypothermia without activating these cold defense mechanisms. Capsinoids are non-pungent TRPV1 agonists that offer particular translational promise due to their reduced potential for activating TRPV1-linked pain pathways. Additionally, the ester group of capsinoids makes them susceptible to rapid breakdown, offering restricted localized action and reducing side effects. Capsinoids may thus provide a more tolerable and regionally targetable approach for pharmacological hypothermia compared with traditional TRPV1 agonists, such as capsaicin. This study examined the efficacy and specificity of capsinoids to induce mild hypothermia in conscious mice. Capsinoids delivered intraperitoneally (IP) quickly induced a TRPV1-dependent drop in core body temperature into the mild hypothermia range (32-34 'C). Importantly, core temperature dropped without triggering cold defense mechanisms (e.g. shivering). The response to capsinoids was dose-dependent and effective in young and aged mice of both sexes. Repeated administration of capsinoids was able to maintain hypothermia for up to 6 hours, supporting the potential for applying this cooling procedure for promoting post-stroke TH. Capsinoid-induced hypothermia was linked to an activation of heat defense mechanisms, evidenced by the rapid induction of cutaneous vasodilation (measured as increased tail temperature immediately following capsinoid delivery) and the subsequent drop in core body temperature. Lastly, we showed that IP capsinoids activate vagal afferents, demonstrated by an increase in c-Fos positive neurons in the nodose ganglion. Collectively, these findings show that capsinoids can pharmacologically induce hypothermia via TRPV1 activation, and thus offer a potential new therapeutic approach to promote TH for ischemic stroke patients.