Inflammatory Pain Promotes Increased Opioid Self-Administration: Role of Dysregulated Ventral Tegmental Area μ Opioid Receptors
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| Názov: | Inflammatory Pain Promotes Increased Opioid Self-Administration: Role of Dysregulated Ventral Tegmental Area μ Opioid Receptors |
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| Autori: | Lucia Hipólito, Adrianne Wilson-Poe, Yolanda Campos-Jurado, Elaine Zhong, Jose Gonzalez-Romero, Laszlo Virag, Robert Whittington, Sandra D. Comer, Susan M. Carlton, Brendan M. Walker, Michael R. Bruchas, Jose A. Morón |
| Zdroj: | The Journal of Neuroscience. 35:12217-12231 |
| Informácie o vydavateľovi: | Society for Neuroscience, 2015. |
| Rok vydania: | 2015 |
| Predmety: | Ventral Tegmental Area - drug effects, Male, Glycine Agents - pharmacology, Receptors, Opioid, mu, Action Potentials, Pain - pathology, Ala-MePhe-Gly- - administration & dosage, Hyperalgesia - drug therapy, Rats, Sprague-Dawley, 0302 clinical medicine, Enkephalin, Receptors, Heroin - administration & dosage, Action Potentials - drug effects, Neurons, Analgesics, Inhibitory Postsynaptic Potentials - drug effects, Quinoxalines - pharmacology, Glycine Agents, 3. Good health, Analgesics, Opioid, Inflammation - complications, Hyperalgesia, mu - metabolism, Excitatory Amino Acid Antagonists - pharmacology, Inflammation - chemically induced, Pain - psychology, Pain Threshold, Neurons - drug effects, Pain, Opioid, 03 medical and health sciences, Ventral Tegmental Area - pathology, Strychnine - pharmacology, Quinoxalines, Animals, Pain Threshold - drug effects, Inflammation, Animal, Enkephalin, Ala(2)-MePhe(4)-Gly(5), Pain - drug therapy, Rats, Heroin, Disease Models, Animal, Inhibitory Postsynaptic Potentials, Operant - drug effects, Ventral Tegmental Area - metabolism, Disease Models, Conditioning, Operant, Sprague-Dawley, Sucrose - administration & dosage, Excitatory Amino Acid Antagonists, Conditioning, Opioid - administration & dosage |
| Popis: | Pain management in opioid abusers engenders ethical and practical difficulties for clinicians, often resulting in pain mismanagement. Although chronic opioid administration may alter pain states, the presence of pain itself may alter the propensity to self-administer opioids, and previous history of drug abuse comorbid with chronic pain promotes higher rates of opioid misuse. Here, we tested the hypothesis that inflammatory pain leads to increased heroin self-administration resulting from altered mu opioid receptor (MOR) regulation of mesolimbic dopamine (DA) transmission. To this end, the complete Freund's adjuvant (CFA) model of inflammation was used to assess the neurochemical and functional changes induced by inflammatory pain on MOR-mediated mesolimbic DA transmission and on rat intravenous heroin self-administration under fixed ratio (FR) and progressive ratio (PR) schedules of reinforcement. In the presence of inflammatory pain, heroin intake under an FR schedule was increased for high, but attenuated for low, heroin doses with concomitant alterations in mesolimbic MOR function suggested by DA microdialysis. Consistent with the reduction in low dose FR heroin self-administration, inflammatory pain reduced motivation for a low dose of heroin, as measured by responding under a PR schedule of reinforcement, an effect dissociable from high heroin dose PR responding. Together, these results identify a connection between inflammatory pain and loss of MOR function in the mesolimbic dopaminergic pathway that increases intake of high doses of heroin. These findings suggest that pain-induced loss of MOR function in the mesolimbic pathway may promote opioid dose escalation and contribute to opioid abuse-associated phenotypes.SIGNIFICANCE STATEMENTThis study provides critical new insights that show that inflammatory pain alters heroin intake through a desensitization of MORs located within the VTA. These findings expand our knowledge of the interactions between inflammatory pain and opioid abuse liability, and should help to facilitate the development of novel and safer opioid-based strategies for treating chronic pain. |
| Druh dokumentu: | Article |
| Popis súboru: | application/pdf |
| Jazyk: | English |
| ISSN: | 1529-2401 0270-6474 |
| DOI: | 10.1523/jneurosci.1053-15.2015 |
| Prístupová URL adresa: | https://www.jneurosci.org/content/jneuro/35/35/12217.full.pdf https://pubmed.ncbi.nlm.nih.gov/26338332 https://www.jneurosci.org/content/jneuro/35/35/12217.full.pdf https://digitalcommons.wustl.edu/cgi/viewcontent.cgi?article=5340&context=open_access_pubs https://www.jneurosci.org/content/35/35/12217.abstract https://www.ncbi.nlm.nih.gov/pubmed/26338332 https://digitalcommons.wustl.edu/open_access_pubs/4336/ http://europepmc.org/articles/PMC4556787 |
| Rights: | CC BY NC SA |
| Prístupové číslo: | edsair.doi.dedup.....2ee623ff4dc8ec5e41a87e543db30644 |
| Databáza: | OpenAIRE |
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Nájsť tento článok vo Web of Science | Abstrakt: | Pain management in opioid abusers engenders ethical and practical difficulties for clinicians, often resulting in pain mismanagement. Although chronic opioid administration may alter pain states, the presence of pain itself may alter the propensity to self-administer opioids, and previous history of drug abuse comorbid with chronic pain promotes higher rates of opioid misuse. Here, we tested the hypothesis that inflammatory pain leads to increased heroin self-administration resulting from altered mu opioid receptor (MOR) regulation of mesolimbic dopamine (DA) transmission. To this end, the complete Freund's adjuvant (CFA) model of inflammation was used to assess the neurochemical and functional changes induced by inflammatory pain on MOR-mediated mesolimbic DA transmission and on rat intravenous heroin self-administration under fixed ratio (FR) and progressive ratio (PR) schedules of reinforcement. In the presence of inflammatory pain, heroin intake under an FR schedule was increased for high, but attenuated for low, heroin doses with concomitant alterations in mesolimbic MOR function suggested by DA microdialysis. Consistent with the reduction in low dose FR heroin self-administration, inflammatory pain reduced motivation for a low dose of heroin, as measured by responding under a PR schedule of reinforcement, an effect dissociable from high heroin dose PR responding. Together, these results identify a connection between inflammatory pain and loss of MOR function in the mesolimbic dopaminergic pathway that increases intake of high doses of heroin. These findings suggest that pain-induced loss of MOR function in the mesolimbic pathway may promote opioid dose escalation and contribute to opioid abuse-associated phenotypes.SIGNIFICANCE STATEMENTThis study provides critical new insights that show that inflammatory pain alters heroin intake through a desensitization of MORs located within the VTA. These findings expand our knowledge of the interactions between inflammatory pain and opioid abuse liability, and should help to facilitate the development of novel and safer opioid-based strategies for treating chronic pain. |
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| ISSN: | 15292401 02706474 |
| DOI: | 10.1523/jneurosci.1053-15.2015 |