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Capsaicin has been suggested to act not only on thin primary afferents but also on the hypothalamus, but the neurotransmitter(s) of central capsaicin-sensitive neurons are unknown. The present study was conducted to determine whether any central, especially hypothalamic, glutamatergic terminals were sensitive to capsaicin. Capsaicin evoked glutamate release from slices of hypothalamus and lumbar dorsal horn, but not cerebellum. Such capsaicin action was Ca2+ dependent and inhibited by the capsaicin antagonist capsazepine. Vanilloid receptor subtype 1 mRNA was widely distributed in the brain, with a marked level in the hypothalamus and cerebellum, but not in the spinal cord. The results suggest that there are glutamatergic terminals sensitive to capsaicin in the hypothalamus.

Capsaicin receptors are expressed in primary sensory neurons and excited by heat and protons. We examined the in¯ammation-induced changes of the level of VR1 capsaicin receptor mRNA in sensory neurons and the sensitivity of primary afferents to capsaicin. Carrageenan treatment induced axonal transport of VR1 mRNA, but not that of preprotachykinin mRNA, from the dorsal root ganglia to central and peripheral axon terminals. The sensitivity of central terminals to capsaicin, which was estimated by measuring the capsaicin-evoked release of glutamate from the dorsal horn, was increased by peripheral in¯ammation, and such an increase was suppressed by inhibiting the RNA translation in the dorsal horn with cycloheximide and an intrathecal injection of VR1 antisense oligonucleotides. Thus, peripheral in¯ammation induces the axonal transport of VR1 mRNA, which may be involved in the hypersensitivity of primary afferents to capsaicin and the production of in¯ammatory hyperalgesia. Keywords: axonal transport, capsaicin sensitivity, carrageenan in¯ammation, glutamate release, primary afferent, VR1 capsaicin receptor mRNA.Subcutaneous injection of carrageenan into the hind paw induces in¯ammation, a decrease in nociceptive threshold (Kayser et al. 1991) and hyperexcitability of primary afferents (Coggeshall et al. 1983). Nociceptive primary afferents are sensitive to capsaicin. Capsaicin induces the excitation of nociceptors (Such and Jancso 1986; Holzer 1991) and the release of pain transmitters such as glutamate (Ueda et al. 1993; and neuropeptides (Yaksh et al. 1980;Saria et al. 1986). Capsaicin receptor is called a`proton sensor' and`hot sensor' because of its sensitivity to protons and heat stimulation, respectively (Caterina et al. 1997). When in¯ammation occurs in the periphery, the concentration of protons is increased in injured tissues. Therefore, the activation of capsaicin receptors on the peripheral terminals of primary afferents may be partly involved in in¯ammatory hyperalgesia (Caterina et al. 2000). With regard to the spinal cord, glutamate (Okano et al. 1998) and neuropeptides (Satoh et al. 1992;Okano et al. 1998) are also involved in in¯ammatory hyperalgesia. Peripheral in¯ammation increases capsaicin-evoked release of glutamate and neuropeptides ) from the dorsal horn. Although an increase in the biosynthesis of neurotransmitters in primary sensory neurons may be partly responsible for an increase in capsaicin-evoked release of the neurotransmitters Ohno et al. 1990), it is unclear whether peripheral in¯ammation alters, especially increases, the sensitivity of primary afferent

Vanilloid receptor subtype 1 (VR1), a capsaicin receptor, is expressed in primary sensory neurons and vagal nerves. Heat and protons as well as capsaicin activate VR1 to induce the influx of cations, particularly Ca2+ and Na+ ions. Characteristic effects of capsaicin are the induction of a burning sensation after acute administration and the desensitization of sensory neurons after large doses and prolonged administration. The latter feature made capsaicin cream applicable for the treatment of chronic pain and pruritus. Capsaicin alters several visceral functions, which may be mediated by action on vagal nerves and central neurons. Capsaicin affects thermoregulation after intra-hypothalamic injection and releases glutamate from the hypothalamus and cerebral cortex slices, while VR1-like immunoreactivity is not apparent in these regions. These findings taken together suggest the existence of other subtypes of vanilloid receptors in the brain.

Patients who have an ischemic stroke are at high risk of swallowing disorders. Aspiration due to swallowing disorders, specifically delayed trigger of the pharyngeal stage of swallowing, predisposes such patients to pneumonia. In the present study, we evaluated swallowing reflex in a rat model of transient middle cerebral artery occlusion (tMCAO), which is one of the most common experimental animal models of cerebral ischemia, in order to develop a novel animal model of dysphagia following ischemic stroke. A swallowing reflex was elicited by a 10-s infusion of distilled water (DW) to the pharyngolaryngeal region in the tMCAO rat model. Swallowing reflex was estimated using the electromyographic activity of the mylohyoid muscle from 1 to 3 weeks after surgery. Two weeks after tMCAO, the number of swallows significantly decreased and the onset latency of the first swallow was prolonged compared with that of the sham group. The number of swallows in rats significantly increased by infusions of 10 mM citric acid and 0.6 μM capsaicin to the pharyngolaryngeal region compared with the number from infusion of DW. It has been reported that sensory stimulation of the pharyngolaryngeal region with citric acid, capsaicin, and L-menthol ameliorates hypofunction of pharyngeal-stage swallowing in dysphagia patients. Therefore, the tMCAO rat model may show some of the symptoms of pharyngeal-stage swallowing disorders, similar to those in patients with ischemic stroke. This rat tMCAO model has the potential to become a novel animal model of dysphagia following stroke that is useful for development of therapeutic methods and drugs.

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The above results suggest that salivatin lowers hyperglycaemia after meal and sustains the normal blood glucose levels by incretin-like mechanisms. The function may be damaged by diabetes, and this in turn might make the diabetes worse.

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