Gábor Jancsó

Co-localization of the vanilloid capsaicin receptor and substance P in sensory nerve fibers innervating cochlear and vertebro-basilar arteries

Evidence suggests that capsaicin-sensitive substance P (SP)-containing trigeminal ganglion neurons innervate the spiral modiolar artery (SMA), radiating arterioles, and the stria vascularis of the cochlea. Antidromic electrical or chemical stimulation of trigeminal sensory nerves results in neurogenic plasma extravasation in inner ear tissues. The primary aim of this study was to reveal the possible morphological basis of cochlear vascular changes mediated by capsaicin-sensitive sensory nerves. Therefore, the distribution of SP and capsaicin receptor (transient receptor potential vanilloid type 1-TRPV1) was investigated by double immunolabeling to demonstrate the anatomical relationships between the cochlear and vertebro-basilar blood vessels and the trigeminal sensory fiber system. Extensive TRPV1 and SP expression and co-localization were observed in axons within the adventitial layer of the basilar artery, the anterior inferior cerebellar artery, the SMA, and the radiating arterioles of the cochlea. There appears to be a functional relationship between the trigeminal ganglion and the cochlear blood vessels since electrical stimulation of the trigeminal ganglion induced significant plasma extravasation from the SMA and the radiating arterioles. The findings suggest that stimulation of paravascular afferent nerves may result in permeability changes in the basilar and cochlear vascular bed and may contribute to the mechanisms of vertebro-basilar type of headache through the release of SP and stimulation of TPVR1, respectively. We propose that vertigo, tinnitus, and hearing deficits associated with migraine may arise from perturbations of capsaicin-sensitive trigeminal sensory ganglion neurons projecting to the cochlea.

β-Amyloid (1–42) peptide impairs blood-brain barrier function after intracarotid infusion in rats

The effects of intracarotid infusions of beta-amyloid (1-42) peptide was studied on the permeability of brain vessels. Using a quantitative Evans blue method a dose-dependent increase of brain tissue albumin content was established following intracarotid injections of the peptide. Cerebral vessels of increased permeability were also demonstrated with a vital staining technique. Lectin histochemistry revealed an almost complete abolition of specific lectin binding sites of affected endothelial cells. The findings indicate a significant deterioration by beta-amyloid (1-42) peptide of blood-brain barrier function and suggest that this may result from endothelial damage. It is assumed that altered permeability of cerebral vessels may be involved in the development of brain pathologies associated with Alzheimers disease.

Capsaicin stimulation of the cochlea and electric stimulation of the trigeminal ganglion mediate vascular permeability in cochlear and vertebro-basilar arteries: a potential cause of inner ear dysfunction in headache

Trigeminal neurogenic inflammation is one explanation for the development of vascular migraine. The triggers for this inflammation and pain are not well understood, but are probably vasoactive components acting on the blood vessel wall. Migraine-related inner ear symptoms like phonophobia, tinnitus, fluctuation in hearing perception and increased noise sensitivity provide indirect evidence that cochlear blood vessels are also affected by basilar artery migraine. The purpose of this investigation was to determine if a functional connection exists between the cochlea and the basilar artery. Neuronally mediated permeability changes in the cochlea and basilar artery were measured by colloidal silver and Evans Blue extravasation, following orthodromic and antidromic stimulation of the trigeminal ganglion innervating the cochlea. Capsaicin and electrical stimulation induced both dose- and time-dependent plasma extravasation of colloidal silver and Evans Blue from the basilar artery and anterior inferior cerebellar artery. Both orthodromic and antidromic activation of trigeminal sensory fibers also induced cochlear vascular permeability changes and significant quantitative differences between the treated and control groups in spectrophotometric assays. These results characterize a vasoactive connection between the cochlea and vertebro-basilar system through the trigeminal sensory neurons. We propose that vertigo, tinnitus and hearing deficits associated with basilar migraine could arise by excitation of the trigeminal nerve fibers in the cochlea, resulting in local plasma extravasation. In addition, cochlear dysfunction may also trigger basilar and cluster headache by afferent input to the trigeminal system.

Significance of the Rate of Systemic Change in Blood Pressure on the Short-Term Autoregulatory Response in Normotensive and Spontaneously Hypertensive Rats

Cerebral autoregulation, the physiological regulatory mechanism that maintains a constant cerebral blood flow (CBF) over wide ranges of arterial blood pressure, was investigated in normotensive and spontaneously hypertensive rats by means of laser-Doppler flowmetry. Systemic arterial hypertension was produced at rates ranging from 0.02 mm Hg/second to 11 mm Hg/second by constant infusion of epinephrine and norepinephrine. Systemic arterial hypotension was produced at rates ranging from -0.03 mm Hg/second to -12 mm Hg/second, either by bleeding the animals into a reservoir or by compressing the abdomen. In those cases with a low rate of change in systemic arterial blood pressure (SABP), the measurements lasted for 5 +/- 2 minutes, and in those with a high rate of change in SABP, measurements lasted for 40 +/- 30 seconds. The purpose was to record the time of onset and course of autoregulation in the basal ganglia in response to slow or rapid changes in SABP. CBF in the basal gray matter remained at baseline values (i.e., autoregulation was functioning) if the rate of increase of SABP did not exceed a critical value (0.10 mm Hg/second in the normotensive rats; 0.35 mm Hg/second in the spontaneously hypertensive rats). When hypertension was produced at faster rates, CBF followed arterial blood pressure passively, and no autoregulatory response was observed for 2 +/- 1 minutes. Hypotension did not change the baseline CBF when it was not produced at a rate faster than -0.4 mm Hg/second in normotensive rats and -0.15 mm Hg/second in spontaneously hypertensive rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Changes in fibre populations of the rat hairy skin following selective chemodenervation by capsaicin

Abstractu2002Perineural application of capsaicin results in a selective and permanent reduction in the sensitivity to noxious chemical and heat stimuli and elimination of the neurogenic inflammatory response. The present quantitative immunohistochemical study has been undertaken to reveal the populations of cutaneous afferent nerves that are affected by perineural capsaicin treatment. Areas of intact and chemodenervated skin were determined with the aid of the vascular labelling technique. In sections taken from intact skin areas, staining with antibodies against protein gene product 9.5 revealed a rich epidermal innervation. Fibres immunoreactive for growth-associated protein 43 were also abundant; nerve fibres immunoreactive for substance P and calcitonin gene-related peptide were less numerous. Somatostatin- and RT97-immunoreactive fibres were seen only in the subepidermal layer. In sections taken from skin areas supplied by the sciatic nerve treated with capsaicin 3 days previously, the number of epidermal nerve fibres immunoreactive to protein gene product 9.5, growth-associated protein 43, substance P and calcitonin gene-related peptide was reduced by 90%, 95%, 97% and 66%, respectively. These changes persisted for at least 42 days. The findings reveal that the majority of epidermal axons are capsaicin-sensitive and comprise a chemically heterogeneous population. Reductions in cutaneous fibre populations following perineural capsaicin treatment may result from both the degeneration of sensory axons and the depletion of neuron-specific macromolecules. In addition, most cutaneous nociceptive axons may not use the major sensory neuropeptides substance P and calcitonin gene-related peptide as afferent neurotransmitters.

Capsaicin treatment induces selective sensory degeneration and increased sympathetic innervation in the rat ureter

Quantitative immunohistochemistry was used to study the innervation of the ureter in adult rats pretreated with capsaicin as neonates (50 mg/kg) or as adults (100-150 mg/kg, 10-22 days prior to being killed) using antibodies against protein gene-product 9.5, neuron-specific enolase, substance P, calcitonin gene-related peptide, neuropeptide Y, dopamine-beta-hydroxylase and vasoactive intestinal polypeptide. The number of calcitonin gene-related peptide- and substance P-containing fibres was reduced in the subepithelial plexus (adult capsaicin treatment < 1%, neonatal treatment < 5% of control), the submucosa (adult treatment < 11%; neonatal treatment < 51%) and in the smooth muscle layer and adventitia (adult treatment < 11%; neonatal treatment < 58%). Fibres immunoreactive for protein gene-product 9.5, a general neuronal marker, were reduced to 11% (adult treatment) or 0.5% (neonatal treatment) in the subepithelial plexus, but unchanged in the other layers, indicating a selective regional degeneration. In the smooth muscle layer the number of neuropeptide Y- and vasoactive intestinal polypeptide-containing nerve fibres was not altered by capsaicin. The number of neuropeptide Y fibres in the subepithelial plexus, however, was significantly increased after adult treatment (174% of control). After neonatal capsaicin treatment the intensity of the neuropeptide Y immunoreactivity was increased, more neuropeptide Y-positive nerve bundles were found and immunoreactive cell bodies were observed regularly in the adventitia of the ureter. The data indicate that capsaicin produces a selective degeneration of most afferent fibres in the subepithelial plexus of the rat ureter. This loss of capsaicin-sensitive afferent nerves evokes neuroplastic changes resulting in a hyperinnervation by neuropeptide Y-immunoreactive, presumably sympathetic fibres. The results suggest a mutual regulation of the pattern and density of innervation of peripheral target tissues by sensory and sympathetic neurons.

INHIBITION OF THE NEUROGENIC INFLAMMATORY RESPONSE BY LIDOCAINE IN RAT SKIN

Axon reflex vasodilatation and neurogenic plasma extravasation are characteristic cutaneous vascular responses mediated by neuropeptides released from stimulated capsaicin-sensitive sensory nerve endings. Intracutaneous injections of local anaesthetics inhibit the axon-reflex flare elicited by chemical irritants in human skin. Results of earlier reports on the effects of local anaesthetics on neurogenic plasma extravasation are controversial. The aim of the present study, therefore, was to re-examine the effect of the local anaesthetic lidocaine on the neurogenic inflammatory response of rat skin. The effects of lidocaine on cutaneous inflammatory reactions were measured quantitatively by means of the Evans blue technique. Intracutaneous injection of lidocaine resulted in a dose-dependent inhibition of the neurogenic inflammation elicited by mustard oil and of the dye leakage response to compound 48/80 or histamine. It is suggested that the site of this inhibition is beyond the sensory nerve terminal, presumably at the level of the vascular endothelium.

Evidence for an inhibition by endogenous galanin of neurogenic cutaneous vasodilatation in the pigeon.

The effect of high affinity galanin antagonist M35 on neurogenic cutaneous vasodilatation has been studied in the pigeon using a Laser Doppler Imager. Cutaneous application of mustard oil or antidromic electrical stimulation of a cutaneous nerve produced a small increase in skin blood flow. Close arterial injection of M35 prior to chemical or electrical stimulation resulted in a marked augmentation of the vasodilatory response. This effect was abolished by chronic denervation. The results suggest a nerve-mediated inhibitory effect of endogenous galanin on neurogenic cutaneous vasodilatation in the pigeon skin and provide the first experimental evidence for an inhibitory local regulatory function of cutaneous sensory nerves at least in the avian skin.

Neurogenic inflammation in the gastrointestinal tract of the rat.

In contrast to the skin and some visceral organs the capability of capsaicin-sensitive sensory nerves of evoking an inflammatory response in the gastrointestinal tract is equivocal. We have therefore investigated the neurogenic plasma extravasation induced by local application of capsaicin to the stomach, duodenum, jejunum, ileum and colon of the rat. Permeable vessels were visualised histologically with the vascular labelling technique using colloidal silver. In the smooth muscle layer of the small intestine, capsaicin elicited a 3-fold increase in the density of labelled blood vessels (diameter, 7-35 microns). Significant capsaicin-evoked plasma extravasation was also observed in the submucosa of the jejunum and ileum, and in the basal layer of the jejunal mucosa. Capsaicin-induced extravasation was not noted in the stomach and the colon. The data suggest the involvement of capsaicin-sensitive afferents in inflammatory processes in the rat small intestine.

Inhibitory modulation of cutaneous vascular responses by endogenous galanin in the pigeon

The possible role of endogenous galanin in modulation of cutaneous vascular responses was studied in pigeons. Chemically induced plasma extravasation and regional skin blood flow changes were measured simultaneously with a capillary perfusion technique and a laser Doppler imager, respectively. Perfusion with both histamine and bradykinin increased plasma protein extravasation which was dose-dependently and significantly augmented by co-administration of M35, a specific galanin antagonist. This effect of M35 was abolished after chronic cutaneous denervation. In intact but not denervated skin, M35 increased the vasodilatatory effect of histamine, too. It is suggested that galanin-containing nerves may play an inhibitory efferent role in the modulation of cutaneous inflammatory responses.