Mária Dux

Capsaicin-sensitive local sensory innervation is involved in pacing-induced preconditioning in rat hearts: role of nitric oxide and CGRP?

Abstract Among several mediators, nitric oxide (NO) and calcitonin gene-related peptide (CGRP) were suggested to be involved in the mechanism of preconditioning. We examined the possible role of the cardiac capsaicin-sensitive sensory innervation in pacing-induced preconditioning, as well as in the cardiac NO and CGRP content. Wistar rats were treated subcutaneously with capsaicin or its solvent in the sequence of 10, 30, and 50 mg/kg increasing single daily doses for 3 days to deplete neurotransmitters of the sensory innervation. Isolated hearts from both groups were then subjected to either preconditioning induced by three consecutive periods of pacing at 600 beats per minute for 5 min with 5 min interpacing periods, or time-matched non-preconditioning perfusion, followed by a 10-min coronary occlusion. NO content of left ventricular tissue samples was assayed by electron-spin resonance, and CGRP release was determined by radioimmunoassay. CGRP immunohistochemistry was also performed. In the non-preconditioned, solvent-treated group, coronary occlusion decreased cardiac output (CO) from 68.1 to 32.1 mL/min, increased left ventricular end-diastolic pressure (LVEDP) from 0.58 to 1.90 kPa, and resulted in 200 mU/min/g LDH release. Preconditioning significantly increased ischaemic CO to 42.9 mL/min (P < 0.05), decreased ischaemic LVEDP to 1.26 kPa (P < 0.05) and decreased LDH release to 47 mU/min/g (P < 0.05) in the solvent-treated group. Preconditioning did not confer protection in the capsaicin-pretreated group (ischaemic CO: 35.6 mL/min; LVEDP: 1.76 kPa; LDH 156 mU/min/g). Capsaicin-treatment markedly decreased cardiac NO content, CGRP release, and CGRP-immunoreactivity. Conclusions: (i) The presence of an intact local sensory innervation is a prerequisite to elicit pacing-induced preconditioning in the rat heart. (ii) A significant portion of cardiac basal NO content may be of neural origin. (iii) Release of NO and CGRP from capsaicin-sensitive nerves may be involved in the mechanism of pacing-induced preconditioning.

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

Abstract Perineural 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.

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.

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.

Axotomy prevents capsaicin-induced sensory ganglion cell degeneration

A particular group of mammalian primary afferent neurons involved in nociception is characterized by its specific sensitivity to capsaicin, the pungent principle of red pepper. A striking manifestation of neuronal capsaicin sensitivity is the degeneration of a morphologically well characterized population of sensory ganglion cells following a systemic injection of this compound. The present study demonstrated that prior transection of the peripheral axons of these neurons protects them from the neurotoxic action of systemically administered capsaicin. It is suggested that this phenomenon is related to an impairment of axon transport mechanisms. It is concluded that maintenance of capsaicin sensitivity is critically dependent on the integrity of the peripheral branch of the primary sensory neuron and peripherally derived trophic factor(s) may profoundly influence the functional traits of sensory ganglion cells.

Role of capsaicin-sensitive afferent nerves in initiation and maintenance of pathological pain

This commentary provides experimental data in support of the critical role of capsaicin-sensitive primary afferent fibers in the initiation and maintenance of pathological pain. The demonstration of capsaicin-induced, centrally-evoked cutaneous hyperalgesia, and of neuroplastic changes elicited by the degeneration of C-fiber primary afferent terminals following peripheral nerve damage, indicates a significant contribution of capsaicin-sensitive sensory ganglion neurons in the development of pathological pain conditions. [coderre & katz]

Synthesis of chicken galanin and its N- and C-terminal segments, and preparation of their antisera

We describe the synthesis of the first aviangalanin (GAL), chicken GAL, and its N-terminal and C-terminal segments by solid-phasesynthesis, using Boc/Bzl amino acidprotection groups and MBHA resin. The three peptides were prepared with purities of over97%, as determined by RP-HPLC, HPCE, FAB-MS or ESI-MSand amino acid analysis.Antibodies against these synthetic peptides wereraised in rabbits and used forimmunohistochemical localization of GAL-immunoreactiveneurons in chicken brain.