A genetic analysis of opioid-induced hyperalgesia in mice
De-Yong Liang, Guochun Liao, Jianmei Wang, Jonathan Usuka, YingYing Guo, Gary Peltz, J David Clark, De-Yong Liang, Guochun Liao, Jianmei Wang, Jonathan Usuka, YingYing Guo, Gary Peltz, J David Clark
Abstract
Background: Opioid-induced hyperalgesia (OIH) is a syndrome of increased sensitivity to noxious stimuli, seen after both the acute and chronic administration of opioids, that has been observed in humans and rodent models. This syndrome may reduce the clinical utility of opioids in treating acute and chronic pain.
Methods: In these studies, the authors measured the propensity of 15 strains of inbred mice to develop mechanical manifestations of OIH. These data were subjected to in silico genetic analysis, which resulted in the association of haplotypic blocks within or near several known genes. Both pharmacologic agents and transgenic mice were used to confirm the functional association of the most strongly linked gene with OIH.
Results: Both baseline mechanical nociceptive thresholds and the percentage changes in these thresholds after 4 days of morphine treatment were found to be highly strain dependent. The haplotypic blocks most strongly associated with the mechanical OIH data were located within the beta2 adrenergic receptor gene (beta2-AR). Using the selective beta2-AR antagonist butoxamine, the authors observed a dose-dependent reversal of OIH. Furthermore, deletion of the beta2-AR gene sharply reduced the mechanical allodynia present after morphine treatment in the wild-type mouse strain. Analysis of the associated beta2-AR haplotypic block identified single nucleotide polymorphisms potentially explaining in part the strain specific differences in OIH.
Conclusions: Genetic variants of the beta2-AR gene seem to explain some part of the differences between various strains of mice to develop OIH. The association of this gene with OIH suggests specific pharmacologic strategies for reducing the impact of OIH on patients consuming opioids.
Figures
![Figure 1](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/1464476/bin/nihms8221f1.jpg)
Figure 2
Haplotypic mapping results using data…
Figure 2
Haplotypic mapping results using data from the 15 strains of mice. For these…
Figure 3
The pharmacological reversal of the…
Figure 3
The pharmacological reversal of the mechanical and thermal manifestations of OIH using the…
Figure 4
The assessment of mechanical and…
Figure 4
The assessment of mechanical and thermal manifestations of OIH in β2-AR null mutant…
Figure 5
The effects of locally injected…
Figure 5
The effects of locally injected β2-AR ligands. In panel A, local injection of…
Figure 6
Diagram of the β2-AR haplotypic…
Figure 6
Diagram of the β2-AR haplotypic block associated with OIH. Arrows indicate the relative…
- Perspectives on the genetic basis of opioid-induced hyperalgesia.Nackley A, Diatchenko L, Maixner W. Nackley A, et al. Anesthesiology. 2006 May;104(5):909-10. doi: 10.1097/00000542-200605000-00004. Anesthesiology. 2006. PMID: 16645440 No abstract available.
- Genetic variants of the P-glycoprotein gene Abcb1b modulate opioid-induced hyperalgesia, tolerance and dependence.Liang DY, Liao G, Lighthall GK, Peltz G, Clark DJ. Liang DY, et al. Pharmacogenet Genomics. 2006 Nov;16(11):825-35. doi: 10.1097/01.fpc.0000236321.94271.f8. Pharmacogenet Genomics. 2006. PMID: 17047491
- The multiple PDZ domain protein Mpdz/MUPP1 regulates opioid tolerance and opioid-induced hyperalgesia.Donaldson R, Sun Y, Liang DY, Zheng M, Sahbaie P, Dill DL, Peltz G, Buck KJ, Clark JD. Donaldson R, et al. BMC Genomics. 2016 Apr 29;17:313. doi: 10.1186/s12864-016-2634-1. BMC Genomics. 2016. PMID: 27129385 Free PMC article.
- The beta2 adrenergic receptor regulates morphine tolerance and physical dependence.Liang DY, Shi X, Li X, Li J, Clark JD. Liang DY, et al. Behav Brain Res. 2007 Jul 19;181(1):118-26. doi: 10.1016/j.bbr.2007.03.037. Epub 2007 Apr 7. Behav Brain Res. 2007. PMID: 17498818 Free PMC article.
- Opioid-induced hyperalgesia: Cellular and molecular mechanisms.Roeckel LA, Le Coz GM, Gavériaux-Ruff C, Simonin F. Roeckel LA, et al. Neuroscience. 2016 Dec 3;338:160-182. doi: 10.1016/j.neuroscience.2016.06.029. Epub 2016 Jun 23. Neuroscience. 2016. PMID: 27346146 Review.
- A comprehensive review of opioid-induced hyperalgesia.Lee M, Silverman SM, Hansen H, Patel VB, Manchikanti L. Lee M, et al. Pain Physician. 2011 Mar-Apr;14(2):145-61. Pain Physician. 2011. PMID: 21412369 Review.
- PACAP-PAC1 receptor inhibition is effective in opioid induced hyperalgesia and medication overuse headache models.Bertels Z, Mangutov E, Siegersma K, Cropper HC, Tipton A, Pradhan AA. Bertels Z, et al. iScience. 2023 Jan 10;26(2):105950. doi: 10.1016/j.isci.2023.105950. eCollection 2023 Feb 17. iScience. 2023. PMID: 36756376 Free PMC article.
- Pharmacological Interventions for Opioid-Induced Hyperalgesia: A Scoping Review of Preclinical Trials.Koponen ME, Forget P. Koponen ME, et al. J Clin Med. 2022 Nov 29;11(23):7060. doi: 10.3390/jcm11237060. J Clin Med. 2022. PMID: 36498635 Free PMC article. Review.
- Machine learning and deep learning frameworks for the automated analysis of pain and opioid withdrawal behaviors.Bumgarner JR, Becker-Krail DD, White RC, Nelson RJ. Bumgarner JR, et al. Front Neurosci. 2022 Sep 26;16:953182. doi: 10.3389/fnins.2022.953182. eCollection 2022. Front Neurosci. 2022. PMID: 36225736 Free PMC article. Review.
- NEURONAL CORRELATES OF HYPERALGESIA AND SOMATIC SIGNS OF HEROIN WITHDRAWAL IN MALE AND FEMALE MICE.Alvarez-Bagnarol Y, Marchette RCN, Francis C, Morales MM, Vendruscolo LF. Alvarez-Bagnarol Y, et al. eNeuro. 2022 Jun 21;9(4):ENEURO.0106-22.2022. doi: 10.1523/ENEURO.0106-22.2022. Online ahead of print. eNeuro. 2022. PMID: 35728954 Free PMC article.
- What Have We Learned (or Expect to) From Analysis of Murine Genetic Models Related to Substance Use Disorders?Peltz G, Tan Y. Peltz G, et al. Front Psychiatry. 2022 Jan 12;12:793961. doi: 10.3389/fpsyt.2021.793961. eCollection 2021. Front Psychiatry. 2022. PMID: 35095607 Free PMC article. Review.
- Research Support, N.I.H., Extramural
- Adrenergic beta-Antagonists / pharmacology
- Analgesics, Opioid / pharmacology*
- Animals
- Butoxamine / pharmacology
- Chromosome Mapping
- Haplotypes
- Hot Temperature
- Hyperalgesia / chemically induced*
- Hyperalgesia / genetics*
- Mice
- Mice, Inbred Strains
- Mice, Knockout
- Mice, Transgenic
- Morphine / pharmacology
- Pain Measurement / drug effects
- Physical Stimulation
- Receptors, Adrenergic, beta-2 / drug effects
- Receptors, Adrenergic, beta-2 / genetics*
- Adrenergic beta-Antagonists
- Analgesics, Opioid
- Receptors, Adrenergic, beta-2
- Butoxamine
- Morphine
- Full Text Sources
- Other Literature Sources
- Medical
- Molecular Biology Databases
NCBI Literature Resources
The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Unauthorized use of these marks is strictly prohibited.
National Library of Medicine
8600 Rockville Pike
Bethesda, MD 20894
![Figure 2](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/1464476/bin/nihms8221f2.jpg)
![Figure 3](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/1464476/bin/nihms8221f3.jpg)
Figure 4
The assessment of mechanical and…
Figure 4
The assessment of mechanical and thermal manifestations of OIH in β2-AR null mutant…
Figure 5
The effects of locally injected…
Figure 5
The effects of locally injected β2-AR ligands. In panel A, local injection of…
Figure 6
Diagram of the β2-AR haplotypic…
Figure 6
Diagram of the β2-AR haplotypic block associated with OIH. Arrows indicate the relative…
- Perspectives on the genetic basis of opioid-induced hyperalgesia.Nackley A, Diatchenko L, Maixner W. Nackley A, et al. Anesthesiology. 2006 May;104(5):909-10. doi: 10.1097/00000542-200605000-00004. Anesthesiology. 2006. PMID: 16645440 No abstract available.
- Genetic variants of the P-glycoprotein gene Abcb1b modulate opioid-induced hyperalgesia, tolerance and dependence.Liang DY, Liao G, Lighthall GK, Peltz G, Clark DJ. Liang DY, et al. Pharmacogenet Genomics. 2006 Nov;16(11):825-35. doi: 10.1097/01.fpc.0000236321.94271.f8. Pharmacogenet Genomics. 2006. PMID: 17047491
- The multiple PDZ domain protein Mpdz/MUPP1 regulates opioid tolerance and opioid-induced hyperalgesia.Donaldson R, Sun Y, Liang DY, Zheng M, Sahbaie P, Dill DL, Peltz G, Buck KJ, Clark JD. Donaldson R, et al. BMC Genomics. 2016 Apr 29;17:313. doi: 10.1186/s12864-016-2634-1. BMC Genomics. 2016. PMID: 27129385 Free PMC article.
- The beta2 adrenergic receptor regulates morphine tolerance and physical dependence.Liang DY, Shi X, Li X, Li J, Clark JD. Liang DY, et al. Behav Brain Res. 2007 Jul 19;181(1):118-26. doi: 10.1016/j.bbr.2007.03.037. Epub 2007 Apr 7. Behav Brain Res. 2007. PMID: 17498818 Free PMC article.
- Opioid-induced hyperalgesia: Cellular and molecular mechanisms.Roeckel LA, Le Coz GM, Gavériaux-Ruff C, Simonin F. Roeckel LA, et al. Neuroscience. 2016 Dec 3;338:160-182. doi: 10.1016/j.neuroscience.2016.06.029. Epub 2016 Jun 23. Neuroscience. 2016. PMID: 27346146 Review.
- A comprehensive review of opioid-induced hyperalgesia.Lee M, Silverman SM, Hansen H, Patel VB, Manchikanti L. Lee M, et al. Pain Physician. 2011 Mar-Apr;14(2):145-61. Pain Physician. 2011. PMID: 21412369 Review.
- PACAP-PAC1 receptor inhibition is effective in opioid induced hyperalgesia and medication overuse headache models.Bertels Z, Mangutov E, Siegersma K, Cropper HC, Tipton A, Pradhan AA. Bertels Z, et al. iScience. 2023 Jan 10;26(2):105950. doi: 10.1016/j.isci.2023.105950. eCollection 2023 Feb 17. iScience. 2023. PMID: 36756376 Free PMC article.
- Pharmacological Interventions for Opioid-Induced Hyperalgesia: A Scoping Review of Preclinical Trials.Koponen ME, Forget P. Koponen ME, et al. J Clin Med. 2022 Nov 29;11(23):7060. doi: 10.3390/jcm11237060. J Clin Med. 2022. PMID: 36498635 Free PMC article. Review.
- Machine learning and deep learning frameworks for the automated analysis of pain and opioid withdrawal behaviors.Bumgarner JR, Becker-Krail DD, White RC, Nelson RJ. Bumgarner JR, et al. Front Neurosci. 2022 Sep 26;16:953182. doi: 10.3389/fnins.2022.953182. eCollection 2022. Front Neurosci. 2022. PMID: 36225736 Free PMC article. Review.
- NEURONAL CORRELATES OF HYPERALGESIA AND SOMATIC SIGNS OF HEROIN WITHDRAWAL IN MALE AND FEMALE MICE.Alvarez-Bagnarol Y, Marchette RCN, Francis C, Morales MM, Vendruscolo LF. Alvarez-Bagnarol Y, et al. eNeuro. 2022 Jun 21;9(4):ENEURO.0106-22.2022. doi: 10.1523/ENEURO.0106-22.2022. Online ahead of print. eNeuro. 2022. PMID: 35728954 Free PMC article.
- What Have We Learned (or Expect to) From Analysis of Murine Genetic Models Related to Substance Use Disorders?Peltz G, Tan Y. Peltz G, et al. Front Psychiatry. 2022 Jan 12;12:793961. doi: 10.3389/fpsyt.2021.793961. eCollection 2021. Front Psychiatry. 2022. PMID: 35095607 Free PMC article. Review.
- Research Support, N.I.H., Extramural
- Adrenergic beta-Antagonists / pharmacology
- Analgesics, Opioid / pharmacology*
- Animals
- Butoxamine / pharmacology
- Chromosome Mapping
- Haplotypes
- Hot Temperature
- Hyperalgesia / chemically induced*
- Hyperalgesia / genetics*
- Mice
- Mice, Inbred Strains
- Mice, Knockout
- Mice, Transgenic
- Morphine / pharmacology
- Pain Measurement / drug effects
- Physical Stimulation
- Receptors, Adrenergic, beta-2 / drug effects
- Receptors, Adrenergic, beta-2 / genetics*
- Adrenergic beta-Antagonists
- Analgesics, Opioid
- Receptors, Adrenergic, beta-2
- Butoxamine
- Morphine
- Full Text Sources
- Other Literature Sources
- Medical
- Molecular Biology Databases
NCBI Literature Resources
The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Unauthorized use of these marks is strictly prohibited.
National Library of Medicine
8600 Rockville Pike
Bethesda, MD 20894
![Figure 4](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/1464476/bin/nihms8221f4.jpg)
Figure 5
The effects of locally injected…
Figure 5
The effects of locally injected β2-AR ligands. In panel A, local injection of…
Figure 6
Diagram of the β2-AR haplotypic…
Figure 6
Diagram of the β2-AR haplotypic block associated with OIH. Arrows indicate the relative…
- Perspectives on the genetic basis of opioid-induced hyperalgesia.Nackley A, Diatchenko L, Maixner W. Nackley A, et al. Anesthesiology. 2006 May;104(5):909-10. doi: 10.1097/00000542-200605000-00004. Anesthesiology. 2006. PMID: 16645440 No abstract available.
- Genetic variants of the P-glycoprotein gene Abcb1b modulate opioid-induced hyperalgesia, tolerance and dependence.Liang DY, Liao G, Lighthall GK, Peltz G, Clark DJ. Liang DY, et al. Pharmacogenet Genomics. 2006 Nov;16(11):825-35. doi: 10.1097/01.fpc.0000236321.94271.f8. Pharmacogenet Genomics. 2006. PMID: 17047491
- The multiple PDZ domain protein Mpdz/MUPP1 regulates opioid tolerance and opioid-induced hyperalgesia.Donaldson R, Sun Y, Liang DY, Zheng M, Sahbaie P, Dill DL, Peltz G, Buck KJ, Clark JD. Donaldson R, et al. BMC Genomics. 2016 Apr 29;17:313. doi: 10.1186/s12864-016-2634-1. BMC Genomics. 2016. PMID: 27129385 Free PMC article.
- The beta2 adrenergic receptor regulates morphine tolerance and physical dependence.Liang DY, Shi X, Li X, Li J, Clark JD. Liang DY, et al. Behav Brain Res. 2007 Jul 19;181(1):118-26. doi: 10.1016/j.bbr.2007.03.037. Epub 2007 Apr 7. Behav Brain Res. 2007. PMID: 17498818 Free PMC article.
- Opioid-induced hyperalgesia: Cellular and molecular mechanisms.Roeckel LA, Le Coz GM, Gavériaux-Ruff C, Simonin F. Roeckel LA, et al. Neuroscience. 2016 Dec 3;338:160-182. doi: 10.1016/j.neuroscience.2016.06.029. Epub 2016 Jun 23. Neuroscience. 2016. PMID: 27346146 Review.
- A comprehensive review of opioid-induced hyperalgesia.Lee M, Silverman SM, Hansen H, Patel VB, Manchikanti L. Lee M, et al. Pain Physician. 2011 Mar-Apr;14(2):145-61. Pain Physician. 2011. PMID: 21412369 Review.
- PACAP-PAC1 receptor inhibition is effective in opioid induced hyperalgesia and medication overuse headache models.Bertels Z, Mangutov E, Siegersma K, Cropper HC, Tipton A, Pradhan AA. Bertels Z, et al. iScience. 2023 Jan 10;26(2):105950. doi: 10.1016/j.isci.2023.105950. eCollection 2023 Feb 17. iScience. 2023. PMID: 36756376 Free PMC article.
- Pharmacological Interventions for Opioid-Induced Hyperalgesia: A Scoping Review of Preclinical Trials.Koponen ME, Forget P. Koponen ME, et al. J Clin Med. 2022 Nov 29;11(23):7060. doi: 10.3390/jcm11237060. J Clin Med. 2022. PMID: 36498635 Free PMC article. Review.
- Machine learning and deep learning frameworks for the automated analysis of pain and opioid withdrawal behaviors.Bumgarner JR, Becker-Krail DD, White RC, Nelson RJ. Bumgarner JR, et al. Front Neurosci. 2022 Sep 26;16:953182. doi: 10.3389/fnins.2022.953182. eCollection 2022. Front Neurosci. 2022. PMID: 36225736 Free PMC article. Review.
- NEURONAL CORRELATES OF HYPERALGESIA AND SOMATIC SIGNS OF HEROIN WITHDRAWAL IN MALE AND FEMALE MICE.Alvarez-Bagnarol Y, Marchette RCN, Francis C, Morales MM, Vendruscolo LF. Alvarez-Bagnarol Y, et al. eNeuro. 2022 Jun 21;9(4):ENEURO.0106-22.2022. doi: 10.1523/ENEURO.0106-22.2022. Online ahead of print. eNeuro. 2022. PMID: 35728954 Free PMC article.
- What Have We Learned (or Expect to) From Analysis of Murine Genetic Models Related to Substance Use Disorders?Peltz G, Tan Y. Peltz G, et al. Front Psychiatry. 2022 Jan 12;12:793961. doi: 10.3389/fpsyt.2021.793961. eCollection 2021. Front Psychiatry. 2022. PMID: 35095607 Free PMC article. Review.
- Research Support, N.I.H., Extramural
- Adrenergic beta-Antagonists / pharmacology
- Analgesics, Opioid / pharmacology*
- Animals
- Butoxamine / pharmacology
- Chromosome Mapping
- Haplotypes
- Hot Temperature
- Hyperalgesia / chemically induced*
- Hyperalgesia / genetics*
- Mice
- Mice, Inbred Strains
- Mice, Knockout
- Mice, Transgenic
- Morphine / pharmacology
- Pain Measurement / drug effects
- Physical Stimulation
- Receptors, Adrenergic, beta-2 / drug effects
- Receptors, Adrenergic, beta-2 / genetics*
- Adrenergic beta-Antagonists
- Analgesics, Opioid
- Receptors, Adrenergic, beta-2
- Butoxamine
- Morphine
- Full Text Sources
- Other Literature Sources
- Medical
- Molecular Biology Databases
![Figure 5](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/1464476/bin/nihms8221f5.jpg)
Figure 6
Diagram of the β2-AR haplotypic…
Figure 6
Diagram of the β2-AR haplotypic block associated with OIH. Arrows indicate the relative…
![Figure 6](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/1464476/bin/nihms8221f6.jpg)
Source: PubMed