Capsaicin-sensitive mechanisms are involved in cortical spreading depression-associated cerebral blood ¯ow changes in rats F. Bari * , D. Paprika, G. Jancso  , F. Domoki Department of Physiology, Faculty of Medicine, University of Szeged, Szeged, H-6720, Do  m te Âr 10, Hungary Received 30 June 2000; received in revised form 4 August 2000; accepted 4 August 2000 Abstract We tested the hypothesis that capsaicin-sensitive mechanisms play a role in the cortical spreading depression (CSD)- related changes in cortical blood ¯ow (CBF). CBF was measured with laser Doppler ¯owmetry in anesthetized rats. The animals were treated with capsaicin before (48 h±2 weeks) or during the experiments. This agent is thought to stimulate small-diameter sensory nerve ®bers selectively and to deplete stored peptides. In the vehicle-treated group (n  8), the peak value of the CSD-associated hyperperfusion was 257 ^ 12% above the baseline (mean ^ SEM, P , 0:05). In the groups treated with 20 and 40 mg/kg or 20 mg/kg capsaicin, there were only small decreases in CBF. In the groups treated with 100 mg/kg capsaicin, the CSD-associated hyperemia was reduced at 48 h (158 ^ 7%, P , 0:05). However, at 96 h a transient hyperresponsiveness (390 ^ 38%, P , 0:05) was observed, which had disappeared by 2 weeks. These results indicate that the manipulation of sensory neuropeptide stores results in a biphasic effect on CSD-induced CBF responses. q 2000 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Capsaicin; Cortical spreading depression; Laser Doppler; Rat; Trigeminal nerve Cortical spreading depression (CSD), propagating at a rate of 2±3 mm/min across the cortical surface, is a transient perturbation of the cortical neuronal activity and cortical blood ¯ow (CBF). CSD, which involves neuronal depolar- ization, the release of neurotransmitters and changes in gene expression, has long been regarded as closely associated with migraine headache with aura [15]. Although several vasoactive substances of various origins are thought to be implicated in CSD-related transient changes in CBF, the mechanism has never been satisfactorily elucidated. Avail- able experimental evidence suggests that, besides the known parenchymal metabolites such as K 1 , adenosine, nitric oxide (NO) and glutamate, vasoactive peptides also in¯u- ence the cerebrovascular tone following CSD. Peptide-containing nerve ®bers have been identi®ed that are closely related to large blood vessels in the dura mater and pia mater [3]. A high proportion of these ®bers is sensory and arises mainly from the ophthalmic (nasociliary) division of the trigeminal nerve. Recent data indicate that chronic transection of the nasociliary nerve results in a signi®cant reduction of CBF during CSD [18]. The mode and speci®city of activation of the trigeminal system during CSD are still debated [9,14]. Studies on the trigeminal system have revealed that neuropeptides, including calcito- nin gene-related peptide (CGRP), are involved in various cerebrovascular functions. CGRP release contributes to cerebral vasodilation during hypotension and electrical stimulation of the trigeminal nerve [2]. CGRP has also been shown to mediate the capsaicin-induced relaxation of the cerebral blood vessels [11]. CSD associated as well as post-occlusive hyperemia and the elevation of cerebral blood ¯ow observed during seizures or after endotoxin exposure are, at least in part, mediated through CGRP receptors [2,4,20]. Capsaicin, a pungent algesic substance, has complex effects on a subpopulation of primary sensory neurons. It has been widely demonstrated that the systemic injection of capsaicin results in stimulation of these nerves, followed by depletion of their peptide content. Capsaicin may also induce neurodegeneration and a permanent loss of certain sensory functions [10]. The contribution of the trigeminal sensory system, with special emphasis on the capsaicin sensitivity of CBF regulation, has long been investigated [8,16]. The effects of acute and chronic capsaicin treatments on the trigeminal nerve function seem controversial and require further examination [17]. The present study was Neuroscience Letters 292 (2000) 17±20 0304-3940/00/$ - see front matter q 2000 Elsevier Science Ireland Ltd. All rights reserved. PII: S0304-3940(00)01424-5 www.elsevier.com/locate/neulet * Corresponding author. Fax: 136-62-545842. E-mail address: bari@phys.szote.u-szeged.hu (F. Bari).