Biomedical subjects

P Geppetti

Publications and source records attributed to P Geppetti.

At least 145 records · Page 8Linked to original sources

PubMed1990

Substance P theory: a unique focus on the painful and painless phenomena of cluster headache.

These studies of cluster headache (CH) focus on two key features of pain transmission: a) sensory nerves when stimulated, as well as the expected afferent transmission, also display an efferent function which affects capillaries, glands, and smooth muscle (of the iris in CH); substance P (SP) and allied transmitters such as Vasoactive Intestinal Peptide (VIP) and Calcitonin Gene-Related Peptide (CGRP) are the main agonists of this dual afferent-efferent function; b) impaired pain transmission (deafferentation-like condition) provokes a rostral spread of neuronal irritability and automatic firing ("quasi epileptic foci") producing a clinical predilection for pain with the generation of "spontaneous" pains along the sensory pathways. The substrates studied in the present experiments are the iris, salivary glands, and nasal mucosa. 1) Iris: the conjunctival instillation of SP induces isocoric miosis both in CH sufferers and in normals, thus excluding gross SP receptoral dysfunction of the iris muscle in CH. Electrical stimulation of extraocular (infratrochlear) endings of the first branch of the trigeminal nerve provokes a miosis, which is significantly less in the symptomatic eye than in the contralateral one. This miosis is ascribed to a retrograde release of SP, induced by electrical stimulation of the trigeminal ophthalmic branch. The relatively poor miosis in the painful eye could correlate with a deficient release of SP from the sensory terminals in the iris. 2) Salivary glands: an increase of substance P-like immunoreactivity is found in the saliva taken from the asymptomatic side, but not from the painful side during a cluster headache attack, thus showing at this level also an asymmetry as previously shown in other head structures. 3) Nasal mucosa: intranasal application of capsaicin, a powerful releaser of SP from sensory terminals, evokes an immediate burning pain in the ipsilateral nasal, ocular, and temporal areas, as well as lacrimation and rhinorrhea. A gradual decrease (tachyphylaxis) of these phenomena is consistently observed after few days of daily nasal administration of capsaicin. When this treatment is applied to CH patients, a rapid decrease in the number and intensity of attacks, and even disappearance of symptoms accompanies the decline of the capsaicin-induced manifestations. Local (nasal) capsaicin, in spite of evoking immediately the same vegetative (rhinorrhea, lacrimation, conjunctival congestion) and in part nociceptive (transient nasal, ocular, temporal burning) phenomena of CH, never has been able to provoke delayed spontaneous-CH like attacks. Such delayed provoked attacks, one of the most pregnant phenomena in CH investigations, are almost constantly evoked by systemic stimuli.(ABSTRACT TRUNCATED AT 400 WORDS)

Capsaicin↗

PubMed1989

The 'efferent' function of capsaicin-sensitive nerves: ruthenium red discriminates between different mechanisms of activation.

We have investigated the ability of Ruthenium Red, an inorganic dye with calcium entry blocking properties, to interfere with the 'efferent' function of capsaicin-sensitive sensory nerves. These nerves were activated in the guinea-pig isolated bronchus (atropine in the bath) or left atria (reserpine-pretreated animals, atropine in the bath) by electrical field stimulation or with capsaicin. Both stimuli produced a contraction of the bronchus and a positive inotropic response in the atria, responses which are mediated by endogenous neuropeptides (tachykinins in the bronchus, calcitonin gene-related peptide in the atria) released from sensory nerves. Ruthenium Red (10 microM for 20 min in both cases) selectively inhibited the responses produced by the administration of capsaicin, while leaving the responses to electrical field stimulation unaffected. Likewise, the bronchoconstrictor response to exogenous neurokinin A and the atrial positive inotropic response to calcitonin gene-related peptide were unaffected by Ruthenium Red. A prejunctional site of action of Ruthenium Red was confirmed in release experiments where the dye strongly inhibited the capsaicin-evoked outflow of calcitonin gene-related peptide, which is taken as a marker of activation in sensory nerves. Together with other observations, these findings support the concept that there are two independent mechanisms for activating the 'efferent' function of sensory nerves, one of which is activated by capsaicin and is Ruthenium Red-sensitive but omega-conotoxin-resistant, while the other is activated by propagated action potentials (field stimulation) and is omega-conotoxin-sensitive and Ruthenium Red-resistant.

Animals↗

PubMed1989

Contractile effect of endothelin on isolated iris sphincter muscle of the pig.

Porcine endothelin (1 nM-0.3 microM) produced a concentration-dependent contraction of the isolated sphincter muscle of the pig iris. Neither atropine (1 microM) nor tetrodotoxin (1 microM) nor pre-exposure of the preparation to 10 microM capsaicin for 15 min affected the endothelin-induced response. We propose that the endothelin-induced contraction of the iris sphincter muscle of the pig is largely due to a direct action on smooth muscle cells and is unrelated to neurogenic myotic mechanisms.

Animals↗

PubMed1989

Thiorphan increases capsaicin-evoked release of substance P from slices of dorsal spinal cord of guinea pig.

Capsaicin-evoked release of substance P-like immunoreactivity (SP-LI) from dorsal horn slices of guinea pig spinal cord was unaffected by incubation with the converting enzyme inhibitor captopril (10 microM). However, incubation with the endopeptidase 24.11 inhibitor, thiorphan (10 microM), induced a 2.44-fold increase of capsaicin-evoked SP-LI release, leaving the capsaicin-evoked release of calcitonin gene-related peptide (CGRP)-LI unchanged. Endopeptidase-24.11 activity was higher in homogenates of the dorsal than ventral spinal cord. Endopeptidase-24.11 might be involved in the inactivation of SP released from central endings of primary sensory neurons.

Animals↗

PubMed1989

Release of VIP- but not CGRP-like immunoreactivity by capsaicin from the human isolated small intestine.

Exposure to capsaicin (1 microM) produced a prompt and sustained release of vasoactive intestinal polypeptide-like immunoreactivity (VIP-LI) from mucosa-free strips of human small intestine (jejunum and ileum). A second application of capsaicin, 60 min later, had no effect indicating complete desensitization, a specific feature of the action of capsaicin on sensory nerves. By contrast no release of calcitonin gene-related peptide (CGRP)-LI was produced upon the first or second application of capsaicin.

Aged↗

PubMed1989

Effects of calcitonin gene-related peptide (CGRP), neurokinin A and neurokinin A (4-10) on the mitogenic response of human peripheral blood mononuclear cells.

(1) We have studied the ability of some regulatory peptides to induce a mitogenic (incorporation of tritiated thymidine) response in human peripheral blood mononuclear cells (PBMC) and to modify the response produced by phytohaemagglutinin (PHA), a well known PBMC mitogen. (2) Human calcitonin gene-related peptide (hCGRP), human or salmon calcitonin (hCT, sCT), neurokinin A (NKA) and neurokinin (4-10) (up to 1 microM for each peptide) did not produce per se any significant PBMC stimulation. (3) hCGRP (0.1 nM-1 microM) produced a concentration dependent enhancement of the response to a submaximal concentration of PHA (1 microgram/ml). On the other hand, hCGRP decreased the mitogenic response to a maximal concentration of PHA (25 micrograms/ml). (4) Neither hCT nor sCT (0.1 nM-1 microM) had a significant influence on the response to PHA (1-25 micrograms/ml). (5) Both NKA and NKA (4-10) produced a concentration-dependent (1 fM-10 pM) enhancement of the response to 1 microgram/ml PHA, while these compounds had no effect on the response to 25 micrograms/ml PHA. (6) These findings suggest a potent modulatory action of CGRP and NKA, two peptides present in sensory and other nerves, on immune function which is possibly mediated via C2 receptors for CGRP and NK-2 tachykinin receptors, respectively.

Adult↗

PubMed1989

Autoradiographic localization of vasoactive intestinal polypeptide receptors in the rat mesenteric vascular tree.

By the use of combined in vitro radioreceptor binding and autoradiographic techniques, we analyzed the pharmacological properties and the anatomical localization of the vasoactive intestinal polypeptide (VIP) receptor in rat superior mesenteric artery and in medium and small mesenteric artery branches. 125I-VIP was bound by sections of rat superior mesenteric artery in a manner consistent with the labeling of specific VIP receptors, with Kd and Bmax values of 0.23 nM and 0.71 pmol/mg protein respectively. Inhibition of 125I-VIP binding with VIP and related peptides gives the following rank order of potency: VIP greater than peptide histidine methionine greater than secretin. Light microscope autoradiography reveals specific VIP binding sites within the medial layer of superior mesenteric artery and its branches. Medium and small sized vessels are richer in 125I-VIP binding sites than the larger ones.

Animals↗

PubMed1989

The effect of calcium free medium and nifedipine on the release of substance P-like immunoreactivity and contractions induced by capsaicin in the isolated guinea-pig and rat bladder.

1. Capsaicin produced a prompt release of substance P-like immunoreactivity (SP-LI) from superfused mucosa-free muscle strips excised from the guinea-pig urinary bladder. A second application of capsaicin had no further effect, indicating desensitization. 2. Neither tetrodotoxin (1 microM) or nifedipine (10 microM) had any inhibitory effect on SP-LI release by capsaicin nor influenced the establishment of the desensitized state. Nifedipine produced per se some SP-LI release. 3. SP-LI release by capsaicin was abolished by incubation in a Calcium(Ca)-free medium containing EDTA (1.0 mM) which also afforded a partial protection toward desensitization. A lower EDTA concentration (0.1 mM) did not suppress SP-LI release by capsaicin but still inhibited desensitization. 4. When the concentration of CaCl2 in the medium was lowered to 1/10-1/100 of that present in normal Krebs solution, capsaicin still evoked a marked SP-LI release and desensitization occurred. In a nominally Ca free medium (maximal Ca concentration due to impurities was 6.7 microM) SP-LI release was still observed and desensitization was incomplete. 5. In a nominally Ca free medium, removal of Mg ions enhanced the SP-LI release induced by capsaicin and enhanced desensitization. 6. In functional studies, nifedipine greatly reduced or abolished the capsaicin- or SP-induced contraction of the rat or guinea-pig isolated bladder but did not prevent desensitization. Likewise, SP-LI depletion in the rat bladder following systemic capsaicin desensitization was not prevented by nifedipine pretreatment. On the other hand, the protective action of Ca free media (containing EDTA) was confirmed in organ bath studies (guinea-pig bladder). 7. These findings indicate that: (a) the requirements of extracellular calcium for activation of neuropeptide release from sensory nerves by capsaicin are very low; (b) both excitation of sensory fibers (SP-LI release) and desensitization are dependent upon the presence of extracellular calcium and (c) L-type voltage-sensitive Ca channels are not likely to be involved in the actions of capsaicin on sensory nerve terminals.

Animals↗

PubMed1989

Calcitonin gene-related peptide in the rat kidney: occurrence, sensitivity to capsaicin, and stimulation of adenylate cyclase.

The occurrence, effects and sensitivity to capsaicin and stimulation of adenylate cyclase of calcitonin gene-related peptide (CGRP) in the rat kidney have been investigated. CGRP-like immunoreactivity was higher in the medulla than in the papilla and the cortex. Capsaicin pretreatment significantly reduced CGRP-like immunoreactivity in the medulla and papilla while a small reduction was found in the cortex. CGRP-immunoreactive nerve fibres were observed surrounding blood vessels and occasionally in the vicinity of renal tubules and between the collecting ducts in the papilla. Some CGRP-immunoreactive fibres were also seen in kidneys from capsaicin-pretreated rats. Infusion of capsaicin (1 microM) through the renal artery of isolated and perfused rat kidney increased the CGRP-like immunoreactivity outflow from the venous effluent. This effect exhibited desensitization at the second challenge with the drug. Infusion of either capsaicin (1 microM) or CGRP (1 microM) reduced the increase of perfusion pressure induced by norepinephrine in isolated perfused rat kidney. Plasma protein extravasation was studied in the various regions of the rat kidney following infusion of capsaicin. No significant change was observed in the medulla, papilla or cortex after capsaicin administration. Adenylate cyclase activity was studied in membrane preparations from cortex, medulla and papilla of rat kidney. Cortical and medullary adenylate cyclase was stimulated in a concentration-dependent manner by salmon calcitonin, rat calcitonin and rat CGRP. Salmon calcitonin in these two areas showed half-maximal effective concentration approximately 1000 times lower and maximal stimulation only slightly higher than those of rat calcitonin and rat CGRP. However, in the papilla, only rat CGRP was able to induce a 60% increase of enzyme activity (half-maximal effective concentration, 19 +/- 1.6 nM). It is concluded that CGRP contained in capsaicin-sensitive sensory nerve may exert a local function in discrete areas of the rat kidney.

Adenylyl Cyclases↗

PubMed1989

Topical versus systemic capsaicin desensitization: specific and unspecific effects as indicated by modification or reflex micturition in rats.

The aim of this study was to determine the acute and delayed effect of topical application of high concentrations of capsaicin on the rat urinary bladder on micturition reflex and compare the effects of "topical" bladder desensitization with those produced by systemic (subcutaneous administration) capsaicin desensitization. On acute application, capsaicin (1-3%) produced a transient bladder contraction, not observed in capsaicin-pretreated rats. After a transient increase in excitability of the micturition reflex, topical capsaicin suppressed micturition and overflow incontinence ensued which was reverted by intravenous injection of 4-aminopyridine. Topical capsaicin also abolished reflex micturition in rats which had been systemically treated with capsaicin as adults (50 mg/kg, 7 days before) and reduced significantly the neurogenic bladder contractions produced by intravenous dimethylphenylpiperazinium or neurokinin A, while the direct (myogenic) response to neurokinin A was unaffected. In rats whose bladder was pre-exposed to 1-3% topical capsaicin (7 days before) the micturition reflex was affected in a manner which is qualitatively and quantitatively similar to that observed in rats treated with capsaicin as adults, e.g. increase in bladder capacity with no change in voiding efficiency. Topical capsaicin desensitization of the rat urinary bladder was shown to produce a selective impairment of bladder sensory nerves without any sign of desensitization in other areas of the body using both functional (hot plate, wiping, plasma extravasation) and neurochemical (determination of substance P-like immunoreactivity) assays. Systemically administered capsaicin (7 days before) had little effect on reflex micturition at 12.5 mg/kg but the change in bladder capacity produced at a dose of 25 mg/kg was comparable with that produced at 350 mg/kg. These findings provide evidence that selective desensitization of peripheral terminals of capsaicin-sensitive nerves of the rat urinary bladder inactivates their sensory and "efferent" function in a manner similar to that observed after systemic capsaicin desensitization in adult rats. The functional deficit of reflex micturition produced in this way can be overcome by increasing the stimulus to void. By contrast, neonatal capsaicin desensitization produced a long lasting abolition of reflex micturition. These data are in keeping with the hypothesis that adult versus neonatal capsaicin desensitization may be used as a tool to distinguish between two sets of sensory nerves in the rat urinary bladder.(ABSTRACT TRUNCATED AT 400 WORDS)

4-Aminopyridine↗

PubMed1989

Beneficial effect of capsaicin application to the nasal mucosa in cluster headache.

Capsaicin application to human nasal mucosa was found to induce painful sensation, sneezing, and nasal secretion. All of these factors exhibit desensitization upon repeated applications. The acute effects induced by capsaicin (300 micrograms/100 microliters) application to the nasal mucosa were studied in healthy volunteers and cluster headache patients. These effects were not different in both nostrils of cluster headache patients as well as in the single nostril of healthy controls. Likewise, the time course of desensitization to the painful sensation and nasal secretion induced by capsaicin applied for five consecutive days in control subjects was almost superimposable to those observed in the nasal mucosa of cluster headache patients. The number of spontaneously occurring attacks was significantly reduced in the 60 days after the end of capsaicin treatment. Whether the beneficial effect induced by capsaicin application to the nasal mucosa could be ascribed to a specific action on sensory neurons remains unknown.

Administration, Intranasal↗

PubMed1989

A comparison of bradykinin- and capsaicin-induced myocardial and coronary effects in isolated perfused heart of guinea-pig: involvement of substance P and calcitonin gene-related peptide release.

1. Bradykinin and capsaicin were compared for their ability to elicit functional effects and to release sensory neuropeptides from guinea-pig isolated perfused hearts. 2. Both bradykinin (10 microM) and capsaicin (1 microM) produced a marked increase in coronary flow, a large positive chronotropic effect and a significant reduction in contractile strength. These actions were associated with a marked release of substance P-like immunoreactivity (SP-LI) and calcitonin gene-related-like immunoreactivity (CGRP-LI). The percentage of the tissue content of SP-LI and CGRP-LI released by each agent was similar, although bradykinin was less effective than capsaicin. The ratio of SP-LI/CGRP-LI released by both agents was similar to that present in cardiac tissue. 3. Neuropeptide release could be evoked only once with capsaicin but at least four times with bradykinin. Also, functional responses to capsaicin underwent desensitization. After either in vitro or systemic capsaicin pretreatment, the release of SP-LI and CGRP-LI by bradykinin was reduced and the positive chronotropic effect of bradykinin was significantly reduced, while the increase in coronary flow and negative inotropic responses remained unchanged. 4. Pretreatment with indomethacin (10 microM) strongly antagonized the release of SP-LI and CGRP-LI by bradykinin and reduced the increase in heart rate. 5. These findings suggest that activation by bradykinin (probably through indirect mechanisms) of capsaicin-sensitive sensory nerves in the heart, leads to a local release of sensory neuropeptides. These neuropeptides, in turn, could participate in determining the complex functional effects of this kinin on cardiac performance.

Animals↗

PubMed1989

Multiple mechanisms in the motor responses of the guinea-pig isolated urinary bladder to bradykinin.

1. Bradykinin (1 nm-1 microM) produced a contraction of bladder strips excised from the dome of the guinea-pig urinary bladder, an effect which was greatly enhanced by removal of the mucosal layer or by thiorphan (10 microM). All subsequent experiments were performed in mucosa-free strips and in the presence of thiorphan. 2. In carbachol (5 microM)-contracted strips, bradykinin produced a concentration (1 nm-1 microM)-dependent transient relaxation. 3. Kallidin was slightly more potent than bradykinin in producing a contraction and a relaxation of the carbachol-induced tone. By contrast, [des-Arg9]-bradykinin, a selective B1 receptor agonist was barely effective up to 1 microM. 4. The contractile response to bradykinin was: (a) unaffected by either tetrodotoxin (1 microM), in vitro capsaicin desensitization (10 microM for 30 min) or apamin (0.1 microM); (b) antagonized by indomethacin (5 microM), the prostaglandin receptor antagonist SC-19220 (100 microM) or the B2 receptor antagonist [D-Arg0, Hyp3, Thi5,8, Phe7]-bradykinin (10 micron) and (c) almost abolished by nifedipine (1 microM). 5. The antagonism of the contractile response to bradykinin produced by indomethacin and SC-19220 was non-additive while that produced by indomethacin and the B2 receptor antagonist was additive. 6. The relaxant response to bradykinin was unaffected by tetrodotoxin, in vitro capsaicin desensitization or indomethacin but antagonized in a competitive manner by the B2 receptor antagonist. Further, this response was abolished by apamin (0.1 microM) but unaffected by glibenclamide (1 microM). 7. Bradykinin (10 microM) produced a consistent release of calcitonin gene-related peptide-like immunoreactivity (CGRP-LI) but not substance P-LI from the guinea-pig bladder muscle. CGRP-LI release by bradykinin was greatly reduced in bladders exposed to indomethacin. [des-Arg9]-bradykinin (10 microM) was ineffective. 8. We conclude that: (a) bradykinin-induced contraction involves activation of both B2 receptors and prostanoid synthesis, via distinct mechanisms which act by inducing calcium influx via nifedipine-sensitive channels; (b) bradykinin-induced relaxation involves activation of B2 receptors and opening of apamin-sensitive potassium channels; (c) bradykinin stimulates sensory nerves in this tissue largely via prostanoid production.

Animals↗

PubMed1989

Arachidonic acid-induced bronchomotor responses are partially mediated by release of sensory neuropeptides from capsaicin-sensitive structures.

Administration of arachidonic acid (AA) both in vitro and in vivo elicited prominent contractile responses in guinea-pig airways, which were markedly reduced after capsaicin desensitization. Furthermore, AA superfusion elicited a significant calcitonin gene-related peptide-like immunoreactivity release from isolated bronchi. It is suggested that at least part of the bronchomotor actions of AA rely upon stimulation of capsaicin-sensitive primary afferents.

Anesthesia↗

PubMed1989

Regional differences in the motor and inflammatory responses to capsaicin in guinea pig airways. Correlation with content and release of substance P-like immunoreactivity.

The motor and inflammatory effects of capsaicin, substance P, and neurokinin A, as well as the content and release of substance P-like immunoreactivity (SP-LI), were assessed in the upper and lower guinea pig trachea and in the main bronchus. Capsaicin-induced motor and inflammatory effects were greater in the lower than in the upper tract of the trachea and much more evident at the bronchial than at the tracheal level. On the other hand, no significant regional differences were observed in the potency and efficacy of tachykinins. SP-LI content was significantly greater in the lower than in the upper tract of the trachea and about five times greater in the bronchus than in the trachea. In each single tracheal preparation, a highly significant correlation was found between the motor effect of capsaicin (but not carbachol) and the SP-LI content. Furthermore, capsaicin-induced release of SP-LI was about eight times greater in bronchial than in tracheal tissues. In view of the strict correlation observed between magnitude of motor and inflammatory actions of capsaicin (but not substance P or neurokinin A) and SP-LI content and release, it is proposed that the regional differences in the response of guinea pig respiratory tissues to activation of capsaicin-sensitive sensory fibers might be mainly prejunctional in origin.

Animals↗

PubMed1989

Regional differences of adenylate cyclase stimulation by calcitonin and calcitonin gene-related peptide in the human kidney.

Calcitonin (CT) gene-related peptide (CGRP)-like immunoreactivity was detected in both the cortex and medullo-papillary portion of human kidneys. The two forms of human CGRP as well as rat CGRP were capable of stimulating renal cortical adenylate cyclase activity in a concentration-related manner, with a half-maximally effective concentration (EC50) similar to that of human CT and approximately 100-1000 times higher than that of salmon CT. However, in the medullo-papillary portion, in which both salmon CT and human CT were inactive, the two forms of human and rat CGRP increased adenylate cyclase activity by 100%, with EC50 values ranging from 36 nmol/L to 1 mumol/L. In cortical membrane preparations the effect of CGRP was additive to that of salmon CT. We concluded that regional differences exist in the effect of CT and CGRP in human renal tissue and that in the medullo-papillary portion and possibly in the cortex, CGRP stimulates adenylate cyclase activity through a CT-independent mechanism.

Adenylyl Cyclases↗

PubMed1988

Release of calcitonin gene-related peptide-like immunoreactivity (CGRP-LI) from organs of the genitourinary tract in rats.

Calcitonin gene-related peptide-like immunoreactivity (CGRP-LI) was detected in the rat urinary bladder, ureter and vas deferens and was depleted by systemic capsaicin desensitization. Exposure to capsaicin in vitro produced a prompt increase in CGRP-LI outflow in superfusates of these tissues, while a second application of the drug was ineffective indicating desensitization. These findings provide further evidence for a transmitter role of CGRP from peripheral endings of sensory nerves and the involvement of CGRP-LI in the specific motor response to capsaicin in the rat genitourinary tract.

Animals↗

PubMed1988

Biochemical, anatomical and functional correlates of postnatal development of the capsaicin-sensitive innervation of the rat urinary bladder.

The postnatal development of substance P-like immunoreactivity (SP-LI) in the urinary bladder (assayed by radioimmunoassay and immunohistochemistry) was investigated in rats and compared with changes in the contractile response to acetylcholine, SP or capsaicin. In adult rats, bladder SP-LI was depleted by systemic capsaicin desensitization or extrinsic bladder denervation indicating that it is completely stored in sensory nerves. Bladder SP-LI was not detected in rat fetuses nor in newborn rats until day 3 of postnatal life (P3). SP-LI increased thereafter to reach, at P20, values approaching 60% of the SP-LI observed in the adult rat. By immunohistochemistry, SP-LI positive varicose fibers were not observed until P13. The contractile response to capsaicin was absent at P0, both in vivo (topical application) and in vitro. In adult rats, the capsaicin-induced bladder contraction was abolished by extrinsic denervation and is produced by release of transmitters from sensory nerves. The amplitude of the capsaicin-induced contraction in the postnatal rat bladder was significantly correlated with SP-LI concentration in the organ. Bladders excised from newborn (P0) or adult rats were equally sensitive to exogenous SP which, in both cases, produced a concentration-related contraction. It is concluded that the postnatal development of the 'efferent' function mediated by capsaicin-sensitive nerves of the rat bladder is strictly related to development of peptidergic sensory innervation.

Acetylcholine↗