title: Capturing the aversive state of cephalic pain preclinically.
abstract: OBJECTIVE
  Preclinical evaluation of headache by behavioral assessment of reward from pain relief.
  
  
  METHODS
  Inflammatory mediators (IMs) or control solution were applied to the rat dura mater to elicit a presumed state of cephalic pain. Hind paw incision was used in separate groups of animals to model noncephalic postsurgical pain. Drugs were given systemically or microinjected within the rostral ventromedial medulla (RVM), nucleus accumbens (NAc), or rostral anterior cingulate cortex (rACC). Peripheral nerve block was produced at the level of the popliteal fossa, and behavior was assessed using evoked sensory stimuli or conditioned place preference (CPP). Immunohistochemistry and brain microdialysis measurements were performed.
  
  
  RESULTS
  Dural IMs produced long-lasting generalized cutaneous allodynia. RVM lidocaine produced CPP, increased NAc c-Fos, and dopamine release selectively in rats receiving dural IMs; CPP was blocked by intra-NAc α-flupenthixol, a dopaminergic antagonist. Intravenous α-calcitonin gene-related peptide (αCGRP)(8-37) produced CPP and elicited NAc dopamine release selectively in rats treated with dural IMs. Prior lesion of the rACC or treatment with systemic sumatriptan or αCGRP(8-37) abolished RVM lidocaine-induced CPP in IM-treated rats. Sumatriptan treatment blocked NAc dopamine release in IM-treated rats receiving RVM lidocaine. Systemic sumatriptan did not alter pain relief-induced CPP in rats with incisional injury.
  
  
  CONCLUSIONS
  Cephalic pain was unmasked in rats by assessment of motivated behavior to seek relief. Relief of pain activates the dopaminergic reward pathway to elicit negative reinforcement of behavior. Medications clinically effective for migraine headache selectively elicit relief of ongoing cephalic, but not postsurgical, noncephalic pain. These studies provide a platform for exploring migraine pathophysiology and for the discovery of new headache therapies.
authors.affiliation: Department of Pharmacology, University of Arizona College of Medicine, Tucson, AZ.
authors.forename: Milena
authors.initials: M
authors.lastname: De Felice
authors.forename: Nathan
authors.initials: N
authors.lastname: Eyde
authors.forename: David
authors.initials: D
authors.lastname: Dodick
authors.forename: Gregory O
authors.initials: GO
authors.lastname: Dussor
authors.forename: Michael H
authors.initials: MH
authors.lastname: Ossipov
authors.forename: Howard L
authors.initials: HL
authors.lastname: Fields
authors.forename: Frank
authors.initials: F
authors.lastname: Porreca
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects* / Q000502:physiology; D006179:Gyrus Cinguli / Q000187:drug effects; D006261:Headache / Q000139:chemically induced / Q000188:drug therapy*; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy; D008012:Lidocaine / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D008845:Microinjections; D009407:Nerve Block; D009714:Nucleus Accumbens / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012201:Reward
chemical_list: D008012:Lidocaine