Mu-opioid receptor and receptor tyrosine kinase crosstalk: Implications in mechanisms of opioid tolerance, reduced analgesia to neuropathic pain, dependence, and reward
Despite the prevalence of opioid misuse, opioids remain the frontline treatment regimen for severe pain. However, opioid safety is hampered by side-effects such as analgesic tolerance, reduced analgesia to neuropathic pain, physical dependence, or reward. These side effects promote development of op...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-12-01
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| Series: | Frontiers in Systems Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fnsys.2022.1059089/full |
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| author | Mackenzie C. Gamble Mackenzie C. Gamble Benjamin R. Williams Navsharan Singh Luca Posa Zachary Freyberg Zachary Freyberg Ryan W. Logan Ryan W. Logan Stephanie Puig |
| author_facet | Mackenzie C. Gamble Mackenzie C. Gamble Benjamin R. Williams Navsharan Singh Luca Posa Zachary Freyberg Zachary Freyberg Ryan W. Logan Ryan W. Logan Stephanie Puig |
| author_sort | Mackenzie C. Gamble |
| collection | DOAJ |
| description | Despite the prevalence of opioid misuse, opioids remain the frontline treatment regimen for severe pain. However, opioid safety is hampered by side-effects such as analgesic tolerance, reduced analgesia to neuropathic pain, physical dependence, or reward. These side effects promote development of opioid use disorders and ultimately cause overdose deaths due to opioid-induced respiratory depression. The intertwined nature of signaling via μ-opioid receptors (MOR), the primary target of prescription opioids, with signaling pathways responsible for opioid side-effects presents important challenges. Therefore, a critical objective is to uncouple cellular and molecular mechanisms that selectively modulate analgesia from those that mediate side-effects. One such mechanism could be the transactivation of receptor tyrosine kinases (RTKs) via MOR. Notably, MOR-mediated side-effects can be uncoupled from analgesia signaling via targeting RTK family receptors, highlighting physiological relevance of MOR-RTKs crosstalk. This review focuses on the current state of knowledge surrounding the basic pharmacology of RTKs and bidirectional regulation of MOR signaling, as well as how MOR-RTK signaling may modulate undesirable effects of chronic opioid use, including opioid analgesic tolerance, reduced analgesia to neuropathic pain, physical dependence, and reward. Further research is needed to better understand RTK-MOR transactivation signaling pathways, and to determine if RTKs are a plausible therapeutic target for mitigating opioid side effects. |
| first_indexed | 2024-04-12T05:00:03Z |
| format | Article |
| id | doaj.art-585f4542de6e47da906dfef65e3d5feb |
| institution | Directory Open Access Journal |
| issn | 1662-5137 |
| language | English |
| last_indexed | 2024-04-12T05:00:03Z |
| publishDate | 2022-12-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Systems Neuroscience |
| spelling | doaj.art-585f4542de6e47da906dfef65e3d5feb2022-12-22T03:47:01ZengFrontiers Media S.A.Frontiers in Systems Neuroscience1662-51372022-12-011610.3389/fnsys.2022.10590891059089Mu-opioid receptor and receptor tyrosine kinase crosstalk: Implications in mechanisms of opioid tolerance, reduced analgesia to neuropathic pain, dependence, and rewardMackenzie C. Gamble0Mackenzie C. Gamble1Benjamin R. Williams2Navsharan Singh3Luca Posa4Zachary Freyberg5Zachary Freyberg6Ryan W. Logan7Ryan W. Logan8Stephanie Puig9Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA, United StatesMolecular and Translational Medicine, Department of Medicine, Boston University School of Medicine, Boston, MA, United StatesDepartment of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA, United StatesDepartment of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA, United StatesDepartment of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA, United StatesDepartment of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, United StatesDepartment of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United StatesDepartment of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA, United StatesCenter for Systems Neuroscience, Boston University, Boston, MA, United StatesDepartment of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA, United StatesDespite the prevalence of opioid misuse, opioids remain the frontline treatment regimen for severe pain. However, opioid safety is hampered by side-effects such as analgesic tolerance, reduced analgesia to neuropathic pain, physical dependence, or reward. These side effects promote development of opioid use disorders and ultimately cause overdose deaths due to opioid-induced respiratory depression. The intertwined nature of signaling via μ-opioid receptors (MOR), the primary target of prescription opioids, with signaling pathways responsible for opioid side-effects presents important challenges. Therefore, a critical objective is to uncouple cellular and molecular mechanisms that selectively modulate analgesia from those that mediate side-effects. One such mechanism could be the transactivation of receptor tyrosine kinases (RTKs) via MOR. Notably, MOR-mediated side-effects can be uncoupled from analgesia signaling via targeting RTK family receptors, highlighting physiological relevance of MOR-RTKs crosstalk. This review focuses on the current state of knowledge surrounding the basic pharmacology of RTKs and bidirectional regulation of MOR signaling, as well as how MOR-RTK signaling may modulate undesirable effects of chronic opioid use, including opioid analgesic tolerance, reduced analgesia to neuropathic pain, physical dependence, and reward. Further research is needed to better understand RTK-MOR transactivation signaling pathways, and to determine if RTKs are a plausible therapeutic target for mitigating opioid side effects.https://www.frontiersin.org/articles/10.3389/fnsys.2022.1059089/fullmu-opioid receptoropioid signalingpaintoleranceneuropathic painphysical dependence |
| spellingShingle | Mackenzie C. Gamble Mackenzie C. Gamble Benjamin R. Williams Navsharan Singh Luca Posa Zachary Freyberg Zachary Freyberg Ryan W. Logan Ryan W. Logan Stephanie Puig Mu-opioid receptor and receptor tyrosine kinase crosstalk: Implications in mechanisms of opioid tolerance, reduced analgesia to neuropathic pain, dependence, and reward Frontiers in Systems Neuroscience mu-opioid receptor opioid signaling pain tolerance neuropathic pain physical dependence |
| title | Mu-opioid receptor and receptor tyrosine kinase crosstalk: Implications in mechanisms of opioid tolerance, reduced analgesia to neuropathic pain, dependence, and reward |
| title_full | Mu-opioid receptor and receptor tyrosine kinase crosstalk: Implications in mechanisms of opioid tolerance, reduced analgesia to neuropathic pain, dependence, and reward |
| title_fullStr | Mu-opioid receptor and receptor tyrosine kinase crosstalk: Implications in mechanisms of opioid tolerance, reduced analgesia to neuropathic pain, dependence, and reward |
| title_full_unstemmed | Mu-opioid receptor and receptor tyrosine kinase crosstalk: Implications in mechanisms of opioid tolerance, reduced analgesia to neuropathic pain, dependence, and reward |
| title_short | Mu-opioid receptor and receptor tyrosine kinase crosstalk: Implications in mechanisms of opioid tolerance, reduced analgesia to neuropathic pain, dependence, and reward |
| title_sort | mu opioid receptor and receptor tyrosine kinase crosstalk implications in mechanisms of opioid tolerance reduced analgesia to neuropathic pain dependence and reward |
| topic | mu-opioid receptor opioid signaling pain tolerance neuropathic pain physical dependence |
| url | https://www.frontiersin.org/articles/10.3389/fnsys.2022.1059089/full |
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