title: Endogenous opioid activity in the anterior cingulate cortex is required for relief of pain.
abstract: Pain is aversive, and its relief elicits reward mediated by dopaminergic signaling in the nucleus accumbens (NAc), a part of the mesolimbic reward motivation pathway. How the reward pathway is engaged by pain-relieving treatments is not known. Endogenous opioid signaling in the anterior cingulate cortex (ACC), an area encoding pain aversiveness, contributes to pain modulation. We examined whether endogenous ACC opioid neurotransmission is required for relief of pain and subsequent downstream activation of NAc dopamine signaling. Conditioned place preference (CPP) and in vivo microdialysis were used to assess negative reinforcement and NAc dopaminergic transmission. In rats with postsurgical or neuropathic pain, blockade of opioid signaling in the rostral ACC (rACC) inhibited CPP and NAc dopamine release resulting from non-opioid pain-relieving treatments, including peripheral nerve block or spinal clonidine, an α2-adrenergic agonist. Conversely, pharmacological activation of rACC opioid receptors of injured, but not pain-free, animals was sufficient to stimulate dopamine release in the NAc and produce CPP. In neuropathic, but not sham-operated, rats, systemic doses of morphine that did not affect withdrawal thresholds elicited CPP and NAc dopamine release, effects that were prevented by blockade of ACC opioid receptors. The data provide a neural explanation for the preferential effects of opioids on pain affect and demonstrate that engagement of NAc dopaminergic transmission by non-opioid pain-relieving treatments depends on upstream ACC opioid circuits. Endogenous opioid signaling in the ACC appears to be both necessary and sufficient for relief of pain aversiveness.
authors.affiliation: Department of Pharmacology, Arizona Health Sciences Center, University of Arizona, Tucson, Arizona 85724, and.
authors.forename: Edita
authors.identifier: http://orcid.org/0000-0002-1497-125X
authors.initials: E
authors.lastname: Navratilova
authors.affiliation: Department of Pharmacology, Arizona Health Sciences Center, University of Arizona, Tucson, Arizona 85724, and.
authors.forename: Jennifer Yanhua
authors.initials: JY
authors.lastname: Xie
authors.affiliation: Department of Pharmacology, Arizona Health Sciences Center, University of Arizona, Tucson, Arizona 85724, and.
authors.forename: Diana
authors.initials: D
authors.lastname: Meske
authors.affiliation: Department of Pharmacology, Arizona Health Sciences Center, University of Arizona, Tucson, Arizona 85724, and.
authors.forename: Chaoling
authors.initials: C
authors.lastname: Qu
authors.affiliation: Department of Pharmacology, Arizona Health Sciences Center, University of Arizona, Tucson, Arizona 85724, and.
authors.forename: Kozo
authors.initials: K
authors.lastname: Morimura
authors.affiliation: Department of Pharmacology, Arizona Health Sciences Center, University of Arizona, Tucson, Arizona 85724, and.
authors.forename: Alec
authors.initials: A
authors.lastname: Okun
authors.affiliation: Department of Pharmacology, Arizona Health Sciences Center, University of Arizona, Tucson, Arizona 85724, and.
authors.forename: Naohisa
authors.identifier: http://orcid.org/0000-0001-6507-8528
authors.initials: N
authors.lastname: Arakawa
authors.affiliation: Department of Pharmacology, Arizona Health Sciences Center, University of Arizona, Tucson, Arizona 85724, and.
authors.forename: Michael
authors.initials: M
authors.lastname: Ossipov
authors.affiliation: Department of Neurology, University of California, San Francisco, San Francisco, California 94143.
authors.forename: Howard L
authors.identifier: http://orcid.org/0000-0002-5989-0760
authors.initials: HL
authors.lastname: Fields
authors.affiliation: Department of Pharmacology, Arizona Health Sciences Center, University of Arizona, Tucson, Arizona 85724, and frankp@u.arizona.edu.
authors.forename: Frank
authors.initials: F
authors.lastname: Porreca
mesh_terms: D000701:Analgesics, Opioid / Q000378:metabolism*; D000818:Animals; D006179:Gyrus Cinguli / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D017551:Microdialysis / Q000379:methods; D008845:Microinjections / Q000379:methods; D009020:Morphine / Q000008:administration & dosage*; D010146:Pain / Q000188:drug therapy / Q000378:metabolism*; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011957:Receptors, Opioid / Q000819:agonists / Q000378:metabolism*
chemical_list: D000701:Analgesics, Opioid; D011957:Receptors, Opioid; D009020:Morphine
keywords: affective dimension of pain; anterior cingulate cortex; neuropathic pain; nucleus accumbens; postsurgical pain; reward