Assessment of PDE4 Inhibitor-Induced Hypothermia as a Correlate of Nausea in Mice
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 k...
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| Format: | Article |
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MDPI AG
2021-12-01
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| Online Access: | https://www.mdpi.com/2079-7737/10/12/1355 |
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| author | Abigail Boyd Ileana V. Aragon Justin Rich Will McDonough Marianna Oditt Daniel Irelan Edward Fiedler Lina Abou Saleh Wito Richter |
| author_facet | Abigail Boyd Ileana V. Aragon Justin Rich Will McDonough Marianna Oditt Daniel Irelan Edward Fiedler Lina Abou Saleh Wito Richter |
| author_sort | Abigail Boyd |
| collection | DOAJ |
| description | 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 <i>per se</i> 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 α<sub>2</sub>-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 α<sub>2</sub>-adrenoceptor antagonist produces the effect of PDE4/PDE4D inactivation on the duration of α<sub>2</sub>-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. |
| first_indexed | 2024-03-10T04:33:42Z |
| format | Article |
| id | doaj.art-68a9b275b8504172a7584ff248764bbd |
| institution | Directory Open Access Journal |
| issn | 2079-7737 |
| language | English |
| last_indexed | 2024-03-10T04:33:42Z |
| publishDate | 2021-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biology |
| spelling | doaj.art-68a9b275b8504172a7584ff248764bbd2023-11-23T03:54:49ZengMDPI AGBiology2079-77372021-12-011012135510.3390/biology10121355Assessment of PDE4 Inhibitor-Induced Hypothermia as a Correlate of Nausea in MiceAbigail Boyd0Ileana V. Aragon1Justin Rich2Will McDonough3Marianna Oditt4Daniel Irelan5Edward Fiedler6Lina Abou Saleh7Wito Richter8Department of Biochemistry & Molecular Biology and Center for Lung Biology, University of South Alabama College of Medicine, Mobile, AL 36688, USADepartment of Biochemistry & Molecular Biology and Center for Lung Biology, University of South Alabama College of Medicine, Mobile, AL 36688, USADepartment of Biochemistry & Molecular Biology and Center for Lung Biology, University of South Alabama College of Medicine, Mobile, AL 36688, USADepartment of Biochemistry & Molecular Biology and Center for Lung Biology, University of South Alabama College of Medicine, Mobile, AL 36688, USADepartment of Biochemistry & Molecular Biology and Center for Lung Biology, University of South Alabama College of Medicine, Mobile, AL 36688, USADepartment of Biochemistry & Molecular Biology and Center for Lung Biology, University of South Alabama College of Medicine, Mobile, AL 36688, USADepartment of Biochemistry & Molecular Biology and Center for Lung Biology, University of South Alabama College of Medicine, Mobile, AL 36688, USADepartment of Biochemistry & Molecular Biology and Center for Lung Biology, University of South Alabama College of Medicine, Mobile, AL 36688, USADepartment of Biochemistry & Molecular Biology and Center for Lung Biology, University of South Alabama College of Medicine, Mobile, AL 36688, USATreatment 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 <i>per se</i> 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 α<sub>2</sub>-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 α<sub>2</sub>-adrenoceptor antagonist produces the effect of PDE4/PDE4D inactivation on the duration of α<sub>2</sub>-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.https://www.mdpi.com/2079-7737/10/12/1355PDE4cAMPnauseaemesishypothermiaanesthesia |
| spellingShingle | Abigail Boyd Ileana V. Aragon Justin Rich Will McDonough Marianna Oditt Daniel Irelan Edward Fiedler Lina Abou Saleh Wito Richter Assessment of PDE4 Inhibitor-Induced Hypothermia as a Correlate of Nausea in Mice Biology PDE4 cAMP nausea emesis hypothermia anesthesia |
| title | Assessment of PDE4 Inhibitor-Induced Hypothermia as a Correlate of Nausea in Mice |
| title_full | Assessment of PDE4 Inhibitor-Induced Hypothermia as a Correlate of Nausea in Mice |
| title_fullStr | Assessment of PDE4 Inhibitor-Induced Hypothermia as a Correlate of Nausea in Mice |
| title_full_unstemmed | Assessment of PDE4 Inhibitor-Induced Hypothermia as a Correlate of Nausea in Mice |
| title_short | Assessment of PDE4 Inhibitor-Induced Hypothermia as a Correlate of Nausea in Mice |
| title_sort | assessment of pde4 inhibitor induced hypothermia as a correlate of nausea in mice |
| topic | PDE4 cAMP nausea emesis hypothermia anesthesia |
| url | https://www.mdpi.com/2079-7737/10/12/1355 |
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