Edelmayer RM, Vanderah TW, Majuta L, Fioravanti B, De Felice M, Chichorro JG, Ossipov MH, King T,Lai J, Kori SH, Nelsen AC, Cannon KE, Heinricher MM, Porreca F (2008) A brainstem generator for cutaneous allodynia associated with migraine headache. Neuroscience 2008 Abstracts 171.15/LL16. Society for Neuroscience, Washington, DC.
Summary: Migraine patients often demonstrate cutaneous allodynia that begins unilaterally and intracranially and spreads, via unknown mechanisms, to contralateral and extracranial body regions. As cutaneous allodynia likely reflects the development of central sensitization, we hypothesized that descending facilitatory influences from the rostral ventromedial medulla (RVM) might underlie the generalized expression of this phenomenon. We employed a modified model of application of inflammatory mediators (IM) to the dura of unanesthetized animals and explored the possible requirement of a brainstem site for expression of generalized cutaneous allodynia. Rats were surgically implanted with two cannulas, one of which permitted the application of IM to the surface of the dura and the other for administration of compounds to the RVM, 7 days after surgery. Tactile withdrawal thresholds of the peri-ocular region of the face as well as the hindpaws were tested pre-surgery, post-surgery, and up to 6 hr after application of IM. Bupivacaine or YM022 (CCK2 receptor antagonist) were administered to the RVM at various times after IM. In some studies dermorphin-saporin was administered as a single microinjection to elicit a cytotoxic effect on presumed pain facilitation cells in the RVM; these rats were tested with IM after a further 28 days. Recordings of RVM “ON” and “OFF” cell activity were also performed in separate groups of naïve animals prior to, and after, IM application to the dura. Dural IM produced robust facial and hindpaw allodynia which peaked after approximately 3 hr and recovered to baseline thresholds by approximately 6 hr. RVM bupivacaine, YMO22, or cytotoxic destruction of pain facilitation cells had no effects on sensory thresholds alone, but prevented or significantly attenuated the expression of IM-induced cutaneous allodynia. In addition, IM applied to the dura produced a sustained increase in the discharge of RVM ON cells while transiently inhibiting OFF cells. Facial and hindpaw allodynia associated with dural stimulation may be a useful surrogate of migraine-associated pain which may be exploited mechanistically for the development of novel therapeutic strategies. The data demonstrate the requirement of descending facilitation from the RVM for the expression of cranial and extracranial cutaneous hypersensitivity and offer direct evidence of brainstem involvement in cutaneous allodynia associated with headache pain.
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