Activation of adenosine A2A or A2B receptors causes hypothermia in mice

Abstract

Extracellular adenosine is a danger/injury signal that initiates protective physiology, such as hypothermia. Adenosine has been shown to trigger hypothermia via agonism at A and A adenosine receptors (AAR, AAR). Here, we find that adenosine continues to elicit hypothermia in mice null for AAR and AAR and investigated the effect of agonism at AAR or AAR. The poorly brain penetrant AAR agonists CGS-21680 and PSB-0777 caused hypothermia, which was not seen in mice lacking AAR. MRS7352, a likely non-brain penetrant AAR antagonist, inhibited PSB-0777 hypothermia. While vasodilation is probably a contributory mechanism, AAR agonism also caused hypometabolism, indicating that vasodilation is not the sole mechanism. The AAR agonist BAY60-6583 elicited hypothermia, which was lost in mice null for AAR. Low intracerebroventricular doses of BAY60-6583 also caused hypothermia, indicating a brain site of action, with neuronal activation in the preoptic area and paraventricular nucleus of the hypothalamus. Thus, agonism at any one of the canonical adenosine receptors, AAR, AAR, AAR, or AAR, can cause hypothermia. This four-fold redundancy in adenosine-mediated initiation of hypothermia may reflect the centrality of hypothermia as a protective response.

The A2A receptor agonist CGS 21680 has beneficial and adverse effects on disease development in a humanised mouse model of graft-versus-host disease

“…The reasons for the different effects of CGS 21680 on mouse weight in these and the current studies compared to those discussed above [34][35][36] remains unknown, but may reflect strain differences. CGS 21680-mediated effects on metabolism and weight were observed in C57BL/6 mice [54,55] and NSG mice (this study), whilst CGS 21680 was reported to have no such effects in CD1, Swiss and DBA/1 mice [34][35][36]. Finally, it should be noted that IL-6 can potentially impact mouse body weight, as genetic deficiency of IL-6 promotes obesity [56].…”

“…In rats, CGS 21680, at the same dose used in the current study, is sufficient to prevent weight gain by reducing food intake [52,53]. Moreover, CGS 21680 at this dose increases energy expenditure in mice to prevent diet-induced obesity [54] and causes hypothermia [55]. The reasons for the different effects of CGS 21680 on mouse weight in these and the current studies compared to those discussed above [34][35][36] remains unknown, but may reflect strain differences.…”

Of mice and men – environmental temperature, body temperature, and treatment of obesity

“…Numerous drugs induce hypothermia (e.g., [33]). Some other compounds elicit hypothermia via mast cell activation [35]. One class is those directly signaling thermoregulatory pathways, such as TRPV1 agonists stimulating sensory neurons, thus misleading the brain that the body is warmer than it actually is [34].…”

“…One class is those directly signaling thermoregulatory pathways, such as TRPV1 agonists stimulating sensory neurons, thus misleading the brain that the body is warmer than it actually is [34]. Some other compounds elicit hypothermia via mast cell activation [35]. The hypothermia from mast cell activation is part of an anaphylactic response, accompanied by hypotension, and hypometabolism and hypothermia in a mouse is sometimes used as an indicator of hypotension.…”

Cannabis sativa Terpenes are Cannabimimetic and Provide Support for the Entourage Effect Hypothesis

“…Seeking to test the involvement of other receptor systems, we tested the role of adenosine A2a receptors (A2a) in terpene-induced hypothermia. Activation of A2a can induce hypothermia, hypolocomotion and cataleptic-like behaviors [22] and many studies have started to investigate the interactions between the cannabinoid and adenosine systems [23][24][25][26][27]. In fact, a known cannabis terpene, D-limonene, is an agonist at the A2a receptor [28].…”