Inflammatory Pain Promotes Increased Opioid Self-Administration: Role of Dysregulated Ventral Tegmental Area μ Opioid Receptors.
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.


CONCLUSIONS
This 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.
Department of Anesthesiology, Columbia University, New York, New York 10032.
Lucia
L
Hipólito
Department of Anesthesiology, Columbia University, New York, New York 10032.
Adrianne
A
Wilson-Poe
Departament de Farmàcia i Tecnología Farmacèutica, Facultat de Farmàcia, Universitat de Farmàcia, 46100 Burjassot, València, Spain.
Yolanda
Y
Campos-Jurado
Department of Anesthesiology, Columbia University, New York, New York 10032.
Elaine
http://orcid.org/0000-0002-4674-1870
E
Zhong
Department of Anesthesiology, Columbia University, New York, New York 10032.
Jose
J
Gonzalez-Romero
Department of Anesthesiology, Columbia University, New York, New York 10032.
Laszlo
L
Virag
Department of Anesthesiology, Columbia University, New York, New York 10032.
Robert
R
Whittington
Department of Psychiatry, Division on Substance Abuse, New York State Psychiatric Institute, College of Physicians and Surgeons of Columbia University, New York, New York 10032.
Sandra D
SD
Comer
Department of Neuroscience & Cell Biology, University of Texas Medical Branch Galveston, Galveston, Texas 77555.
Susan M
SM
Carlton
Department of Psychology and Graduate Program in Neuroscience, Washington State University, Pullman, Washington 99164, and.
Brendan M
BM
Walker
Department of Anesthesiology and Department of Anatomy and Neurobiology, Washington University Pain Center, Washington University School of Medicine, St. Louis, Missouri 63110.
Michael R
MR
Bruchas
Department of Anesthesiology, Columbia University, New York, New York 10032, jmc@anest.wustl.edu.
Jose A
JA
Morón
D000200:Action Potentials / Q000187:drug effects; D000701:Analgesics, Opioid / Q000008:administration & dosage*; D000818:Animals; D003216:Conditioning, Operant / Q000187:drug effects; D004195:Disease Models, Animal; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000008:administration & dosage*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018684:Glycine Agents / Q000494:pharmacology; D003932:Heroin / Q000008:administration & dosage; D006930:Hyperalgesia / Q000188:drug therapy; D007249:Inflammation / Q000139:chemically induced / Q000150:complications; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects; D008297:Male; D009474:Neurons / Q000187:drug effects; D010146:Pain / Q000188:drug therapy / Q000473:pathology / Q000523:psychology; D017288:Pain Threshold / Q000187:drug effects; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017450:Receptors, Opioid, mu / Q000378:metabolism*; D013331:Strychnine / Q000494:pharmacology; D013395:Sucrose / Q000008:administration & dosage; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology
D000701:Analgesics, Opioid; D018691:Excitatory Amino Acid Antagonists; D018684:Glycine Agents; D011810:Quinoxalines; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D013395:Sucrose; C056723:FG 9041; D003932:Heroin; D013331:Strychnine
VTA; dopamine; opioids; pain; self-administration; μ opioid receptor