The role of peripheral transient receptor potential vanilloid 1 channels in stress-induced hyperthermia in rats subjected to an anxiogenic environment

https://doi.org/10.1016/j.jtherbio.2022.103191Get rights and content

Highlights

  • TRPV1 modulates thermoregulatory and behavioral responses under stressful conditions.

  • Peripheral TRPV1 desensitization augments anxiety-like behavior in an open field test.

  • TRPV1 desensitized rats show a more pronounced stress-induced hyperthermia.

  • Peripheral TRPV1 desensitization enhances skin vasoconstriction in an open field test.

Abstract

Anxiety resulting from psychogenic stimuli elicit stress-induced hyperthermia in rats, often called “psychogenic fever”, which is part of a coordinated response to situations seen as novel or distressing. Brain transient receptor potential vanilloid 1 (TRPV1) channels modulate both thermoregulation and animal behavior; however, the role of peripheral TRPV1 channels in regulating these responses during exposure to an anxiogenic environment has not been determined. Thus, the present study aimed to investigate the involvement of abdominal TRPV1 channels in stress-induced hyperthermia and behavior in rats subjected to an unconditioned anxiety test. Desensitized rats (peripheral desensitization of TRPV1 channels with resiniferatoxin; RTX) and their respective controls were subjected to a 15-min open field (OF) test. The core body temperature (Tcore), tail skin temperature (Tskin), and rats’ movements inside the arena were recorded. The OF test induced a similar increase in Tcore in both groups throughout the exposure time; however, at the recovery period, the RTX-treated rats had a slower reduction in Tcore due to lower tail skin heat loss. Tskin decreased significantly in both groups during exposure to OF but, during recovery, the RTX-treated rats showed impaired skin vasodilation. Also, RTX-treated rats entered fewer times and spent less time in the OF center square, suggesting an anxiety-related behavior. Our findings indicate that, under stressful conditions, peripheral TRPV1 channels modulate thermoregulatory and behavioral responses. The TRPV1 desensitization induces a more prolonged hyperthermic response due to lower cutaneous heat dissipation, alongside a more evident anxiety-like behavior in rats subjected to the OF apparatus.

Introduction

Anxiety can be defined as a negative emotional state induced by the presence or anticipation of a threat. Thus, anxiety allows animals to cope with potentially dangerous situations (Ennaceur, 2014; Lecorps et al., 2016). In response to anxiogenic stimuli, core body temperature (Tcore) increases due to autonomic activation (Marks et al., 2009; Shibata and Nagasaka, 1982; Vianna and Carrive, 2005; Vinkers et al., 2009a), which is called psychological stress-hyperthermia. During the latter condition, Tcore consistently increases 1.5–2.0 °C, even without involving physical discomfort, and repeated exposure to anxiogenic stimuli does not alter this hyperthermic response (Groenink et al., 2009; Soszynski et al., 1996; Vinkers et al., 2009a).

In humans, stress-induced hyperthermia can be considered a psychosomatic symptom, often called “psychogenic fever” (Nakamura, 2015). Clinical case studies have reported that half of the “fever of unknown origin” cases are psychogenic, and this fever does not respond to antipyretic drugs but to psychotherapy or psychotropic drugs that display anxiolytic and sedative properties (Nozu and Uehara, 2005; Oka, 2015).

Thermoregulation is critical for mammalian survival in a variety of thermal environments. Small oscillations in Tcore within the physiological range often occur during behavior (Madden et al., 2012). These small oscillations are thought to be physiologically relevant; for instance, they may improve synaptic processing necessary for making complex cognitive and emotional decisions that ensure safe and productive execution of exploratory episodes (Blessing and Ootsuka, 2016). However, considerable deviations in cellular temperature can alter molecular properties, thus impairing cellular function and leading to loss of motor coordination and consciousness, respiratory and cardiovascular dysfunction, and eventual death (Burke and Hanani, 2012; Madden et al., 2012).

Tcore maintenance results from the balance between heat production and heat dissipation, which are controlled by the activation or inhibition of thermoregulatory effectors. This balance depends on changes in temperature perceived by thermosensitive receptors, such as the ion channels termed transient receptor potential (TRP), located in the skin, internal organs, and central nervous system (Mekjavic and Eiken, 2006; Nagashima et al., 2000).

Six TRP subfamilies have been identified, among them, the vanilloid receptor subfamily (Hudson et al., 2016; Romanovsky et al., 2009). The transient receptor potential vanilloid 1 (TRPV1) channels are polymodal channels activated by thermal stimuli (in vitro temperatures >43 °C), voltage, low pH, capsaicin, resiniferatoxin (RTX), and endovanilloids (Caterina et al., 1997; Dhaka et al., 2009; Szallasi and Blumberg, 1989). TRPV1 activation causes a transient influx of ions, thereby promoting depolarization of the cell membrane (Caterina and Julius, 2001; Numazaki and Tominaga, 2004; Szallasi and Blumberg, 1999). Several studies have shown TRPV1 channels, including those located in the abdominal cavity, play an important role in regulating Tcore, by activating compensatory heat dissipation mechanisms to avoid exaggerated hyperthermia (Garami et al., 2018; McGaraughty et al., 2009; Steiner et al., 2007). For instance, activation of systemic TRPV1 channels decreases Tcore in rats under basal conditions (Almeida et al., 2006). It also attenuates stress-induced hyperthermia by handling and pricking a mouse with a needle (Garami et al., 2011), whereas TRPV1-desensitized rats have augmented hyperthermia when passively exposed to a hot environment or following exposure to stressful conditions (Jancso-Gabor et al., 1970a). Also, several brain regions, including those involved in thermoregulation, express TRPV1 channels (Kauer and Gibson, 2009; Martins et al., 2014; Toth et al., 2005). The widespread presence of these receptors in the prefrontal cortex, amygdala, and hippocampus (Kauer and Gibson, 2009; Martins et al., 2014; Toth et al., 2005) suggests these channels might be involved in behavioral neurobiology, including anxiety-related behaviors. However, it is unclear whether peripheral TRPV1 channels contribute to regulating animal behavior.

Although previous studies have shown peripheral TRPV1 channels are an integral part of thermoregulation, the role played by these channels in stress-induced hyperthermia has not been described. Likewise, the relationship between stress-induced hyperthermia and animal behavior is still unclear. Based on these premises, we hypothesized that the desensitization of peripheral TRPV1 channels would attenuate the thermoregulatory response for heat dissipation in an unfamiliar aversive environment, potentiating the stress-induced hyperthermia and changing rats’ behavior. Thus, the present study aimed to test the role of peripheral TRPV1 channels in stress-induced hyperthermia and behavior in rats subjected to an unconditioned anxiety test.

Section snippets

Ethics statement

All experimental procedures were approved by the Ethics Commission for the Use of Animals of the Federal University of Ouro Preto (protocol number 2016/32) and were conducted following the regulations provided by the National Council for Animal Experimentation Control (CONCEA/Brazil).

Animals

Adult male Wistar rats (n = 29), weighing 250–350 g, were group-housed (4 animals per cage) at a room temperature of 23 ± 1 °C under 12-h light/12-h dark cycles and had free access to water and rat chow. The rats

Results

As illustrated in Fig. 2, the rats treated with RTX showed a marked reduction in food intake on the first three days post-treatment (F(1,27) = 15.428; p < 0.001), which in turn, led to a reduced body mass during the ensuing week (F(1,27) = 15.428; p < 0.01). The food intake in RTX-treated rats was no longer different from the control group four days after the treatment. The body mass started to increase again in desensitized rats on the fourth day after the treatment, attaining the

Discussion

The present study shows abdominal TRPV1 channels are important in modulating thermal and behavioral responses induced by a stressful condition. When subjected to an unconditioned anxiety test (OF test), desensitized rats showed a more prolonged hyperthermic response due to reduced cutaneous heat dissipation. They also showed more pronounced anxiety-like behavior than the control group during exposure to at novel environment.

The use of pharmacological tools represents a strategy to evaluate the

Conclusion

Our findings highlight that peripheral TRPV1 channels are important in modulating thermoregulatory and behavioral responses under stressful conditions. The desensitization of these receptors induces a more prolonged hyperthermic response by attenuating cutaneous heat dissipation mechanisms, as well as an augmented anxiety-like behavior in rats when subjected to the OF apparatus, which is a behavioral test for studying unconditioned anxiety in rodents due to the exposure to a novel unfamiliar

Author contributions

Paulo Lima: Conceptualization, Methodology, Formal analysis, Investigation, Resources, Data curation, Writing, and Visualization.

Thayane Reis: Investigation and Resources.

Samuel Wanner: Writing, reviewing and editing; Visualization.

Deoclecio Chianca-Jr.: Writing, reviewing and editing.

Rodrigo Menezes: Writing, reviewing and editing; Visualization; Supervision.

Declaration of competing interest

None.

Acknowledgments

The authors are thankful to Marly Lessa and Milton de Paula for their technical assistance. This study was supported by grants from CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico), CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior), FAPEMIG (Fundação de Amparo à Pesquisa do Estado de Minas Gerais), and UFOP (Universidade Federal de Ouro Preto).

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