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. 2023 Mar 29;10(1):136-154.
doi: 10.1080/23328940.2023.2171671. eCollection 2023.

The neural pathway of the hyperthermic response to antagonists of the transient receptor potential vanilloid-1 channel

Andras Garami  1   2 , Alexandre A Steiner  1   3 , Eszter Pakai  1   2 , Samuel P Wanner  1 , M Camila Almeida  1 , Patrik Keringer  2 , Daniela L Oliveira  1 , Kazuhiro Nakamura  4 , Shaun F Morrison  5 , Andrej A Romanovsky  1   6   7
Affiliations

The neural pathway of the hyperthermic response to antagonists of the transient receptor potential vanilloid-1 channel

Andras Garami et al. Temperature (Austin). .

Abstract

We identified the neural pathway of the hyperthermic response to TRPV1 antagonists. We showed that hyperthermia induced by i.v. AMG0347, AMG 517, or AMG8163 did not occur in rats with abdominal sensory nerves desensitized by pretreatment with a low i.p. dose of resiniferatoxin (RTX, TRPV1 agonist). However, neither bilateral vagotomy nor bilateral transection of the greater splanchnic nerve attenuated AMG0347-induced hyperthermia. Yet, this hyperthermia was attenuated by bilateral high cervical transection of the spinal dorsolateral funiculus (DLF). To explain the extra-splanchnic, spinal mediation of TRPV1 antagonist-induced hyperthermia, we proposed that abdominal signals that drive this hyperthermia originate in skeletal muscles - not viscera. If so, in order to prevent TRPV1 antagonist-induced hyperthermia, the desensitization caused by i.p. RTX should spread into the abdominal-wall muscles. Indeed, we found that the local hypoperfusion response to capsaicin (TRPV1 agonist) in the abdominal-wall muscles was absent in i.p. RTX-desensitized rats. We then showed that the most upstream (lateral parabrachial, LPB) and the most downstream (rostral raphe pallidus) nuclei of the intrabrain pathway that controls autonomic cold defenses are also required for the hyperthermic response to i.v. AMG0347. Injection of muscimol (inhibitor of neuronal activity) into the LPB or injection of glycine (inhibitory neurotransmitter) into the raphe blocked the hyperthermic response to i.v. AMG0347, whereas i.v. AMG0347 increased the number of c-Fos cells in the raphe. We conclude that the neural pathway of TRPV1 antagonist-induced hyperthermia involves TRPV1-expressing sensory nerves in trunk muscles, the DLF, and the same LPB-raphe pathway that controls autonomic cold defenses.

Keywords: TRPV1 blockers; Thermoregulation; hyperthermia; protons; skeletal muscle; spinal cord; splanchnic; vagus.

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Conflict of interest statement

A.A.R. is an officer and director of Catalina Pharma, Inc. and Zharko Pharma, Inc.; he has consulted for TRPV1 programs at several pharmaceutical companies, and his laboratory conducted paid research on TRPV1 for Amgen Inc., Abbott Laboratories, and AbbVie Inc.

Figures

Figure 1.
Figure 1.
TRPV1 antagonist-induced hyperthermia is abolished in rats with localized abdominal desensitization of TRPV1 channels with a low dose of i.p. RTX. Rats pretreated with vehicle (sham-desensitized) responded to the i.v. administration of AMG0347 (a), AMG 517 (b), or AMG8163 (c) with a pronounced Tb rise, whereas no hyperthermic response occurred in rats desensitized with i.p. RTX (20 μg/kg). Doses of the TRPV1 antagonists used are indicated. In each panel, data plotted to the right of the temperature curves show two responses of the same sham-desensitized and desensitized rats that were used to study the hyperthermic effect of the corresponding TRPV1 antagonist: 1) the number of writhes (during 10 min) induced by the i.p. administration of RTX (0.1 μg/kg) and 2) the number of eye-wiping movements (during 5 min) induced by the epicorneal application of RTX solution (2 μg/ml, 20 μl). In all panels (a-c), vehicle-pretreated rats had a strong writhing reflex, whereas this reflex was absent in rats pretreated with i.p. RTX, thus confirming successful desensitization of TRPV1 channels in the peritoneal cavity by the latter pretreatment. In contrast, there was no difference between RTX-desensitized and sham-desensitized animals in the eye-wiping test, indicating that extra-abdominal TRPV1 channels were not affected by the i.p. RTX pretreatment. Here and in Figures 2–4, numbers in parentheses are the numbers of animals in the corresponding groups, and the data are presented as the mean ± SE.
Figure 2.
Figure 2.
TRPV1 antagonist-induced hyperthermia is not affected by either total subdiaphragmatic truncal vagotomy or bilateral transection of the greater splanchnic nerve. (a) Sham-vagotomized rats and rats with total subdiaphragmatic truncal vagotomy responded to the i.v. administration of AMG0347 (dose indicated) with nearly identical rises in Tb. Confirming the effectiveness of vagotomy, the stomach mass was drastically increased in vagotomized rats, as compared to sham-vagotomized controls (right portion of panel a). (b) Sham-splanchnicotomized rats and rats with bilateral transection of the greater splanchnic nerve responded to the i.v. administration of AMG0347 with similar Tb rises. Confirming the effectiveness of splanchnicotomy, the blood corticosterone response to 48-h water deprivation was dampened in splanchnicotomized rats, as compared to sham-splanchnicotomized controls (right portion of panel b).
Figure 3.
Figure 3.
TRPV1 antagonist-induced hyperthermia is attenuated by bilateral cervical transection of the DLF of the spinal cord. (a) Rats with complete bilateral cervical dorsolateral funiculotomy responded to i.v. AMG0347 (dose indicated) with a much smaller Tb rise than either sham-funiculotomized controls or rats with incomplete cervical dorsolateral funiculotomy. Data plotted in the right part of panel a show that the tail-flick response to noxious (−18°C) cold was delayed in rats with complete or incomplete dorsolateral funiculotomy, as compared to sham-funiculotomized controls. (b) A schematic of a transversal C1 spinal section from Paxinos and Watson [46] and a representative bright-field photomicrograph of a C1 section with a complete bilateral lesion of the DLF from a rat used in this study (50 μm, cresyl violet). The targeted lesion area on each side of the spinal cord (DLF) is hatched with orange lines; only rats having a lesion covering >50% of the targeted area on each side were considered having “complete” funiculotomy. DF, LF, VF – dorsal, lateral, or ventral funiculus, respectively. (c) Rats with complete dorsolateral funiculotomy did not respond with hyperthermia to a TRPV1 antagonist but mounted robust thermogenic and hyperthermic responses to a β3 agonist. On the left, individual Tb curves show that the hyperthermic response to i.v. AMG0347 (dose indicated) occurred in rats with an intact or partially lesioned DLF but not is rats with complete dorsolateral funiculotomy. Nevertheless, even rats with complete funiculotomy were capable of sporadically developing sharp rises in deep Tb (indicated by arrowheads). On the right, individual deep Tb and VO2 curves show that the hyperthermic and thermogenic responses to i.v. CL316243 (β3-adrenergic receptor agonist; dose indicated) did not differ between rats with sham, incomplete, or complete dorsolateral funiculotomy.
Figure 4.
Figure 4.
The hypoperfusion response in the external oblique abdominal muscle to topical application of a TRPV1 agonist is abolished in rats desensitized with a low dose of i.p. RTX. (a) The upper curves in the left portion show that a rapid and profound decrease in blood flow in the external oblique abdominal muscle in response to topical administration of capsaicin (dose indicated) occurs in rats pretreated with vehicle (sham-desensitized) but not in rats pretreated with i.p. RTX (20 μg/kg) to induce localized abdominal TRPV1 desensitization. The lower curve shows that, in three randomly selected sham-desensitized rats, i.m. capsaicin caused no changes in the carotid blood pressure. Data plotted in the right portion of panel a show two responses of the same sham-desensitized and desensitized rats that were used in the perfusion experiment: 1) the number of writhes (during 10 min) induced by the i.p. administration of RTX (0.1 μg/kg) and 2) the number of eye-wiping movements (during 1 min) induced by the epicorneal application of capsaicin solution (10 μg/ml, 40 μl). Vehicle-pretreated rats had a strong writhing reflex, whereas this reflex was absent in rats pretreated with i.p. RTX, thus confirming successful desensitization of TRPV1 channels in the peritoneal cavity by the latter pretreatment. In contrast, there was no difference between sham-desensitized and RTX-desensitized rats in the eye-wiping test, indicating that extra-abdominal, at least corneal, TRPV1 channels were not affected by the i.p. RTX pretreatment. (b) Individual speckle photographs of the abdominal wall represent perfusion responses to capsaicin and vehicle of sham-desensitized and i.p. RTX-desensitized rats. For each rat and each treatment, a representative baseline (before-treatment) image is shown on the left, and a representative after-treatment (at 60 s after the i.m. administration of vehicle or capsaicin) is shown on the right.
Figure 5.
Figure 5.
The signals driving TRPV1 antagonist-induced hyperthermia travel through the brain via the established neural pathways that control autonomic thermoeffectors. (a) Individual curves demonstrate that the i.v. administration of AMG0347 (the dose is indicated) caused relatively long-lasting (the time-scale bar is shown) increases in BAT SNA and TBAT in an anesthetized rat (top panel). Rats represented in the middle and lower panels received the same i.v. administration of AMG0347 (not shown) as the rat represented in the top panel and 7–12 min later received either an injection of muscimol (dose indicated) into the LPB (middle panel) or an injection of glycine (dose indicated) into the rRPa (lower panel). Either treatment rapidly decreased both BAT SNA and TBAT. The bar graph at the bottom of panel a shows that the mean TBAT increase induced by i.v. AMG0347 was markedly attenuated by either intra-LPB injection of muscimol or intra-rRPa injection of glycine. (b) AMG0347 increased c-Fos expression in the rRPa. Main structures of the rRPa-containing brain area are outlined in the schematic from Paxinos and Watson [43] on the left; py – pyramidal tract; RMg – raphe magnus nucleus. To the right of the schematic, representative photomicrographs of the same brain area show c-Fos-positive neurons. The sections were obtained from rats treated with vehicle or i.v. AMG0347 (dose indicated) in a near-thermoneutral environment, or exposed to severe cold (ambient temperature is indicated; positive control). The bar graph at the bottom of panel b shows that the number of c-Fos-positive cells in the rRPa was higher in rats treated with i.v. AMG0347 at thermoneutrality or exposed to cold, as compared to rats injected with vehicle at thermoneutrality.
Figure 6.
Figure 6.
In rats, the proposed neural pathway of TRPV1 antagonist-induced hyperthermia starts with TRPV1 channels in skeletal muscles of the trunk, goes through the DLF of the spinal cord, and, at an unknown spinal or brainstem site, joins the established LPB-rRPa pathway that drives thermogenesis. Alternative pathways rejected by the present study are shown in red. For each experiment of the present study, the tested pathway, or the tested portion of a pathway, is indicated.
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