Capturing the aversive state of cephalic pain preclinically

Milena De Felice, Nathan Eyde, David William Dodick, Gregory O. Dussor, Michael H. Ossipov, Howard L. Fields, Frank Porreca

Research output: Contribution to journalArticle

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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. Interpretation 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.

Original languageEnglish (US)
Pages (from-to)257-265
Number of pages9
JournalAnnals of Neurology
Volume74
Issue number2
DOIs
StatePublished - Aug 2013

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Headache
Nucleus Accumbens
Sumatriptan
Lidocaine
Pain
Dopamine
Gyrus Cinguli
Migraine Disorders
Reward
Flupenthixol
Dura Mater
Dopamine Antagonists
Nerve Block
Hyperalgesia
Microdialysis
Pain Measurement
Peripheral Nerves
Therapeutics
Animal Models
Immunohistochemistry

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

Cite this

De Felice, M., Eyde, N., Dodick, D. W., Dussor, G. O., Ossipov, M. H., Fields, H. L., & Porreca, F. (2013). Capturing the aversive state of cephalic pain preclinically. Annals of Neurology, 74(2), 257-265. https://doi.org/10.1002/ana.23922

Capturing the aversive state of cephalic pain preclinically. / De Felice, Milena; Eyde, Nathan; Dodick, David William; Dussor, Gregory O.; Ossipov, Michael H.; Fields, Howard L.; Porreca, Frank.

In: Annals of Neurology, Vol. 74, No. 2, 08.2013, p. 257-265.

Research output: Contribution to journalArticle

De Felice, M, Eyde, N, Dodick, DW, Dussor, GO, Ossipov, MH, Fields, HL & Porreca, F 2013, 'Capturing the aversive state of cephalic pain preclinically', Annals of Neurology, vol. 74, no. 2, pp. 257-265. https://doi.org/10.1002/ana.23922
De Felice M, Eyde N, Dodick DW, Dussor GO, Ossipov MH, Fields HL et al. Capturing the aversive state of cephalic pain preclinically. Annals of Neurology. 2013 Aug;74(2):257-265. https://doi.org/10.1002/ana.23922
De Felice, Milena ; Eyde, Nathan ; Dodick, David William ; Dussor, Gregory O. ; Ossipov, Michael H. ; Fields, Howard L. ; Porreca, Frank. / Capturing the aversive state of cephalic pain preclinically. In: Annals of Neurology. 2013 ; Vol. 74, No. 2. pp. 257-265.
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