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Assessment of PDE4 Inhibitor-Induced Hypothermia as a Correlate of Nausea in Mice
Abigail Boyd1, Ileana V Aragon1, Justin Rich1
1Department of Biochemistry & Molecular Biology and Center for Lung Biology, University of South Alabama College of Medicine, Mobile, AL 36688, USA.
Abstract:
Treatment with PAN-PDE4 inhibitors has been shown to produce hypothermia in multiple species. Given the growing body of evidence that links nausea and emesis to disturbances in thermoregulation in mammals, we explored PDE4 inhibitor-induced hypothermia as a novel correlate of nausea in mice. Using knockout mice for each of the four PDE4 subtypes, we show that selective inactivation of individual PDE4 subtypes per se does not produce hypothermia, which must instead require the concurrent inactivation of multiple (at least two) PDE4 subtypes. These findings contrast with the role of PDE4s in shortening the duration of α2-adrenoceptor-dependent anesthesia, a behavioral surrogate previously used to assess the emetic potential of PDE4 inhibitors, which is exclusively affected by inactivation of PDE4D. These different outcomes are rooted in the distinct molecular mechanisms that drive these two paradigms; acting as a physiologic α2-adrenoceptor antagonist produces the effect of PDE4/PDE4D inactivation on the duration of α2-adrenoceptor-dependent anesthesia, but does not mediate the effect of PDE4 inhibitors on body temperature in mice. Taken together, our findings suggest that selective inhibition of any individual PDE4 subtype, including inhibition of PDE4D, may be free of nausea and emesis.
Insights
Phosphodiesterase 4 (PDE4) inhibitors can cause hypothermia, a potential indicator of nausea. However, this study reveals that inhibiting only one PDE4 subtype, including PDE4D, may not cause hypothermia or nausea.
Area of Science:
- Pharmacology
- Neuroscience
- Physiology
Background:
- Phosphodiesterase 4 (PDE4) inhibitors are known to induce hypothermia in various species.
- Nausea and emesis are increasingly linked to disruptions in mammalian thermoregulation.
- PDE4 inhibitors have been assessed for emetic potential using $\alpha_2$-adrenoceptor-dependent anesthesia duration as a surrogate.
Purpose of the Study:
- To investigate phosphodiesterase 4 (PDE4) inhibitor-induced hypothermia as a novel correlate for nausea in mice.
- To determine the specific PDE4 subtypes involved in PDE4 inhibitor-induced hypothermia.
- To compare the mechanisms underlying hypothermia and anesthesia duration changes induced by PDE4 inhibitors.
Main Methods:
- Utilized knockout mice for each of the four PDE4 subtypes (PDE4A, PDE4B, PDE4C, PDE4D).
- Assessed body temperature changes following PDE4 inhibitor treatment.
- Compared the effects of single versus multiple PDE4 subtype inactivation on hypothermia.
- Evaluated the role of PDE4 subtypes in $\alpha_2$-adrenoceptor-dependent anesthesia duration.
Main Results:
- Selective inactivation of any single PDE4 subtype did not produce hypothermia.
- Concurrent inactivation of at least two PDE4 subtypes was required to induce hypothermia.
- In contrast, inactivation of PDE4D alone was sufficient to shorten $\alpha_2$-adrenoceptor-dependent anesthesia duration.
- The mechanisms for hypothermia and anesthesia duration effects are distinct and not mediated by a simple $\alpha_2$-adrenoceptor antagonism.
Conclusions:
- PDE4 inhibitor-induced hypothermia requires the simultaneous inhibition of multiple PDE4 subtypes.
- Selective inhibition of individual PDE4 subtypes, including PDE4D, may be devoid of hypothermic effects.
- These findings suggest that targeting single PDE4 subtypes could potentially avoid nausea and emesis associated with PDE4 inhibition.
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