title: Activation of mesocorticolimbic reward circuits for assessment of relief of ongoing pain: a potential biomarker of efficacy.
abstract: Preclinical assessment of pain has increasingly explored operant methods that may allow behavioral assessment of ongoing pain. In animals with incisional injury, peripheral nerve block produces conditioned place preference (CPP) and activates the mesolimbic dopaminergic reward pathway. We hypothesized that activation of this circuit could serve as a neurochemical output measure of relief of ongoing pain. Medications commonly used clinically, including gabapentin and nonsteroidal anti-inflammatory drugs (NSAIDs), were evaluated in models of post-surgical (1 day after incision) or neuropathic (14 days after spinal nerve ligation [SNL]) pain to determine whether the clinical efficacy profile of these drugs in these pain conditions was reflected by extracellular dopamine (DA) release in the nucleus accumbens (NAc) shell. Microdialysis was performed in awake rats. Basal DA levels were not significantly different between experimental groups, and no significant treatment effects were seen in sham-operated animals. Consistent with clinical observation, spinal clonidine produced CPP and produced a dose-related increase in net NAc DA release in SNL rats. Gabapentin, commonly used to treat neuropathic pain, produced increased NAc DA in rats with SNL but not in animals with incisional, injury. In contrast, ketorolac or naproxen produced increased NAc DA in animals with incisional but not neuropathic pain. Increased extracellular NAc DA release was consistent with CPP and was observed selectively with treatments commonly used clinically for post-surgical or neuropathic pain. Evaluation of NAc DA efflux in animal pain models may represent an objective neurochemical assay that may serve as a biomarker of efficacy for novel pain-relieving mechanisms.
authors.affiliation: Department of Pharmacology, Arizona Health Sciences Center, University of Arizona, Tucson, AZ, USA Department of Anesthesiology, Arizona Health Sciences Center, University of Arizona, Tucson, AZ, USA Departments of Anesthesia and Radiology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Jennifer Y
authors.initials: JY
authors.lastname: Xie
authors.forename: Chaoling
authors.initials: C
authors.lastname: Qu
authors.forename: Amol
authors.initials: A
authors.lastname: Patwardhan
authors.forename: Michael H
authors.initials: MH
authors.lastname: Ossipov
authors.forename: Edita
authors.initials: E
authors.lastname: Navratilova
authors.forename: Lino
authors.initials: L
authors.lastname: Becerra
authors.forename: David
authors.initials: D
authors.lastname: Borsook
authors.forename: Frank
authors.initials: F
authors.lastname: Porreca
mesh_terms: D000588:Amines / Q000494:pharmacology / Q000627:therapeutic use; D000700:Analgesics / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology / Q000627:therapeutic use; D004298:Dopamine / Q000378:metabolism*; D000077206:Gabapentin; D008297:Male; D017551:Microdialysis; D009437:Neuralgia / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D010146:Pain / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012201:Reward; D016896:Treatment Outcome; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000588:Amines; D000700:Analgesics; D015415:Biomarkers; D003509:Cyclohexanecarboxylic Acids; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin; D004298:Dopamine
keywords: Biomarker; Dopamine; Neuropathic pain; Nucleus accumbens; Pain; Pain relief; Post-surgical pain; Rats