Hypothermia in mouse is caused by adenosine A1 and A3 receptor agonists and AMP via three distinct mechanisms

Abstract

Small mammals have the ability to enter torpor, a hypothermic, hypometabolic state, allowing impressive energy conservation. Administration of adenosine or adenosine 5'-monophosphate (AMP) can trigger a hypothermic, torpor-like state. We investigated the mechanisms for hypothermia using telemetric monitoring of body temperature in wild type and receptor knock out (Adora1−/−, Adora3−/−) mice. Confirming prior data, stimulation of the A3 adenosine receptor (AR) induced hypothermia via peripheral mast cell degranulation, histamine release, and activation of central histamine H1 receptors. In contrast, A1AR agonists and AMP both acted centrally to cause hypothermia. Commonly used, selective A1AR agonists, including N6-cyclopentyladenosine (CPA), N6-cyclohexyladenosine (CHA), and MRS5474, caused hypothermia via both A1AR and A3AR when given intraperitoneally. Intracerebroventricular dosing, low peripheral doses of Cl-ENBA [(±)-5'-chloro-5'-deoxy-N6-endo-norbornyladenosine], or using Adora3−/− mice allowed selective stimulation of A1AR. AMP-stimulated hypothermia can occur independently of A1AR, A3AR, and mast cells. A1AR and A3AR agonists and AMP cause regulated hypothermia that was characterized by a drop in total energy expenditure, physical inactivity, and preference for cooler environmental temperatures, indicating a reduced body temperature set point. Neither A1AR nor A3AR were required for fasting-induced torpor. A1AR and A3AR agonists and AMP trigger regulated hypothermia via three distinct mechanisms.

Tremorolytic effect of 5′‐chloro‐5′‐deoxy‐(±)‐ENBA, a potent and selective adenosine A1 receptor agonist, evaluated in the harmaline‐induced model in rats

“…However, we noticed that the highest dose of this compound strongly depressed motor behavior of rats, which did not seem to result solely from its strong sedative effect. Moreover, although we did not measure body temperature of rats, we noted by palpation a slight hypothermia induced by this dose which was in agreement with a recent study in mice . Appearance of these disturbances of 5′Cl5′d‐(±)‐ENBA in rats which were not described (with the exception for the above hypothermia) in mice may suggest species differences in metabolism of this drug.…”

A3 Adenosine Receptors as Modulators of Inflammation: From Medicinal Chemistry to Therapy

“…Activation of the A 3 AR induced hypothermia through the induction of mast cell degranulation, consequent histamine release, and activation of central histamine H 1 receptors …”

Purinergic drug targets for gastrointestinal disorders

“…However, most commonly used AR ligand tools were discovered by empirical approaches (Figure 2, Jacobson and Müller, 2016; Ochoa-Cortes et al, 2016). Cl-ENBA (number 3 in Figure 2) is a more selective A 1 AR agonist for in vivo use than 1 and 2 (Carlin et al, 2017). CGS21680 (not shown) is an A 2A AR agonist in rat, but has substantial human (h) A 3 AR affinity (Alnouri et al, 2015).…”

“…Selective human A 2A AR agonist PBS-0777 7 is water-soluble and does not diffuse across biological membranes. MRS5698 11 is a more selective A 3 AR agonist than 9 and 10 (Carlin et al, 2017). Selective antagonists are available for all four ARs ( 12 – 21 ), but their affinity is often species dependent.…”