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Biomedical subjects

A Dray

Publications and source records attributed to A Dray.

At least 91 records · Page 5Linked to original sources
PubMed1988

Bradykinin-induced stimulation of afferent fibres is mediated through protein kinase C.

In an in vitro preparation of the neonatal spinal cord with the tail attached, brief administration of bradykinin or capsaicin in the tail superfusate containing a normal calcium concentration, activated peripheral fibres and produced a depolarization recorded at a spinal ventral root (L3-L5). Perfusion with a phorbol ester (4 beta-phorbol 12,13-dibutyrate, PDBu) produced a small and inconsistent activation of peripheral fibres. In subsequent experiments calcium was omitted from the tail superfusate since under this condition responses to bradykinin and capsaicin were unchanged but PDBu evoked reproducible depolarization when applied at intervals of 60 min or more. Prolonged desensitization followed repeated administration at shorter intervals. Pretreatment of the tail with capsaicin, to impair transmission in C-fibres, abolished the effect of each agonist. Inactivation of protein kinase C with the inhibitor staurosporine (10-100 nM) attenuated the effect of bradykinin and PDBu but not that of capsaicin. Pretreatment with PDBu also attenuated the effect of bradykinin. These data suggest that a phorbol ester and bradykinin stimulate capsaicin-sensitive C-fibres by a mechanism which involves the activation of protein kinase C.

Alkaloids↗
PubMed1988

Actions of neuropeptide K and calcitonin gene-related peptide on inferior mesenteric ganglion cells--tachykinin interactions with non-cholinergic potentials evoked by ureteric nerve stimulation.

Neuropeptide K (NPK) induced a slow depolarization in principal ganglion cells of the guinea pig inferior mesenteric ganglion (IMG) in vitro. This effect was due to a postsynaptic action and prevented by pre-exposure of the IMG to neurokinin A (NKA) or substance P (SP). The non-cholinergic slow postsynaptic excitatory potential (s-EPSP) evoked by ureteric nerve stimulation was depressed during NPK, SP or NKA application. Calcitonin gene-related peptide (CGRP) applied in concentrations up to 10 microM had no effect on the membrane potential in 90% of IMG cells nor did it influence the s-EPSP. We suggest that NPK may depolarize IMG neurones via similar mechanisms/in a similar fashion, to other tachykinins and that the s-EPSP, induced by stimulation of the afferent ureteric nerve fibres, is mediated by a tachykinin whereas there is little indication/evidence for an involvement of CGRP.

Action Potentials↗
PubMed1988

Bradykinin activates peripheral capsaicin-sensitive fibres via a second messenger system.

A preparation of the neonatal rat spinal cord with attached tail was maintained in vitro and was used to study the mechanism of action of bradykinin on peripheral nociceptors. Spinal ventral root depolarization was used as an index of peripheral fibre activation. Capsaicin-sensitive fibres in the tail were activated by bradykinin and a phorbol ester. The protein kinase C inhibitor staurosporine attenuated the effect of bradykinin and phorbol. [Des-Arg9]-bradykinin was inactive but bradykinin responses were reversibly antagonized by D-Arg0-Hyp2-Thi5,8-D Phe7-bradykinin. These data suggest that bradykinin activates nociceptors via a bradykinin B2-receptor coupled to protein kinase C.

Alkaloids↗
PubMed1988

Non-cholinergic synaptic potentials mediated by lumbar colonic nerve in the guinea-pig inferior mesenteric ganglion in vitro.

Non-cholinergic slow synaptic potentials mediated by the lumbar colonic nerve have been investigated using an in vitro preparation of the guinea-pig inferior mesenteric ganglion attached to a distal colonic segment. Non-cholinergic potential responses to colonic nerve stimulation, colonic distension and chemical activation of sensory afferents were recorded intracellularly from neurons in the inferior mesenteric ganglion. Electrical stimulation of the lumbar colonic nerve produced either a slow excitatory postsynaptic potential, or a slow inhibitory postsynaptic potential followed by a slow excitatory postsynaptic potential. The extrapolated reversal potential of the slow excitatory postsynaptic potential was in the range of 0 to -20 mV and that of the slow inhibitory postsynaptic potential was -90 to 110 mV. The slow excitatory postsynaptic potential and the slow inhibitory postsynaptic potential were reversibly abolished by perfusion of the ganglion with tetrodotoxin (1 microM), or perfusion with low calcium (200 microM), high magnesium (12 mM) containing solution. Capsaicin (1 microM) evoked a reversible depolarization of inferior mesenteric ganglion cells after which desensitization occurred and the slow excitatory postsynaptic potential was abolished but the slow inhibitory postsynaptic potential was enhanced in amplitude and prolonged in duration. Bath application of substance P (2 microM) evoked a prolonged depolarization of inferior mesenteric ganglion neurons, during which the slow excitatory postsynaptic potential but not the slow inhibitory postsynaptic potential was abolished. Distensions of the colon to pressures in the range of 2-25 cm of water produced a stimulus graded non-cholinergic slow depolarization which was occasionally followed by a late slow hyperpolarization. Both types of response were abolished by tetrodotoxin.(ABSTRACT TRUNCATED AT 250 WORDS)

Action Potentials↗
PubMed1988

The involvement of afferent nerve terminals in the stimulation of ion transport by bradykinin in rat isolated colon.

1. The actions of bradykinin (Bk) were investigated on rat colon epithelium preparations that had been stripped of the muscle layers. The electrogenic ion flux was monitored by measuring changes in the short circuit current (SCC) produced by addition of drugs. Bk, administered to the basolateral side, but not apical side, of the epithelium evoked an increase in SCC which was separable into two distinct components, both of which were mediated mainly by chloride efflux. 2. The early component was robust, reproducible and exhibited clear concentration-dependency with an EC50 of 6.2 nM. The second phase of the response exhibited a much slower time course than the first phase and diminished amplitude with repeated applications of Bk. 3. In preparations of unstripped epithelium, bradykinin (Bk) evoked mainly a slow neurogenic response which was attenuated or abolished by tetrodotoxin (TTX). When the epithelium was stripped off, TTX had little effect either on the baseline SCC or on responses to Bk. 4. Perfusion with zero calcium solution did not affect the early phase but abolished the late phase of the Bk response. Verapamil (20 microM), but not nifedipine (20 microM), also attenuated the later phase of the response. 5. Capsaicin (2 microM) administered to the basolateral, but not the apical, side produced an increase in SCC. Following desensitization to capsaicin the second phase of the response to Bk was abolished with little effect on the initial response to Bk. 6. The data suggest that Bk increases the efflux of chloride ions across the colonic epithelium in at least two ways: (a) by an action on the epithelial cells and (b) by an action on neuronal elements within the epithelium. This latter effect of Bk is due to stimulation of capsaicin-sensitive nerve terminals within the mucosa of the colon epithelium causing the release of a mediator which is responsible for the second phase of the response to Bk.

Animals↗
PubMed1988

Activation of a bradykinin receptor in peripheral nerve and spinal cord in the neonatal rat in vitro.

In an in vitro preparation of the neonatal rat spinal cord with attached tail, administration of bradykinin (Bk) to the spinal cord or to the tail produced depolarization of a ventral root (L3-L5). The effect of Bk at each site was selectively and reversibly antagonized by D-Arg [Hyp2, Thi5,8 D-Phe7]-Bk but could not be mimicked or antagonized by the B1-receptor ligands [des-Arg9]-Bk or Leu8[des-Arg9]-Bk, respectively. Peripherally evoked noxious responses produced by capsaicin or heat, were unaffected by either antagonist administered to the spinal cord. These data suggest that Bk-evoked responses in the spinal cord and at peripheral nociceptors were mediated via a receptor which by definition is of the B2-type. Additionally Bk is unlikely to be a physiological mediator of acute nociception in the spinal cord.

Animals↗
PubMed1988

Stimulation of afferent fibres of the guinea-pig ureter evokes potentials in inferior mesenteric ganglion neurones.

1. Intracellular recordings were made from neurones of the guinea-pig inferior mesenteric ganglion (IMG) maintained in vitro with both ureters and major nerve trunks attached. Afferent fibres in the ureteric nerve were activated by electrical, chemical and mechanical stimuli. 2. Repetitive stimulation of a ureteric nerve branch evoked a non-cholinergic, synaptic slow excitatory potential (slow EPSP) in 48% of neurons. The amplitude of the slow EPSP was dependent on membrane potential and was decreased by membrane depolarization and increased by hyperpolarization. 3. The slow EPSP was attenuated or abolished by capsaicin (1 microM), which itself depolarized IMG neurones. Substance P (2 microM) or neurokinin A (2 microM) also depolarized IMG neurones and in the presence of these tachykinins the slow EPSP was attenuated or abolished. 4. Distension of the ureter evoked a non-cholinergic slow depolarization in 45% of IMG neurones which was abolished by tetrodotoxin (1 microM) and by capsaicin (1 microM). 5. Chemical stimulation of ureteric afferent nerve terminals by intralumenal perfusions of the ureter with capsaicin (1 microM) produced a slow depolarization in the IMG which was prevented by blocking nerve conduction with TTX. 6. These data demonstrate that electrical stimulation of ureteric afferent fibres produces a non-cholinergic slow EPSP in the IMG. Primary afferent (capsaicin-sensitive) C fibres are also activated by distension of the ureter and evoke a slow depolarization in the IMG. The synaptic mediator of these events is likely to be tachykinin(s) released from capsaicin-sensitive C fibres. These fibres may be mechanosensory and/or nociceptive.

Animals↗
PubMed1987

Naloxonazine and opioid-induced inhibition of reflex urinary bladder contractions.

Spontaneous volume-induced contractions of the urinary bladder were recorded isometrically in urethane-anesthetized rats. Contractions were inhibited by alternate submaximal but equieffective doses of the selective mu and delta-opioid ligands [D-Ala2-Me-Phe4,Gly(ol)5] enkephaline (DAGO) and [2-D-penicillamine, 5-D-penicillamine] enkephalin (DPDPE), respectively, administered by the intracerebroventricular (i.c.v.) or spinal intrathecal (i.t.) route. Naloxonazine, postulated to be an irreversible mu 1-opioid receptor antagonist, administered by the same route, antagonized the effects of both DAGO and DPDPE. The antagonism of the effect of DAGO was reversed 3-4 hr later but that of DPDPE was more prolonged. Recovery of the effect of DPDPE was observed some 24 hr later. A similar pattern of activity against DAGO and DPDPE given intraventricularly or intrathecally was observed following intravenous injection of naloxonazine (10 mg/kg). Also naloxonazine (i.c.v., i.t. or i.v.) antagonized the effect of morphine given intraventricularly or intrathecally, but antagonism was not observed when morphine was retested 3-4 hr and 24 hr later. Naloxonazine increased the frequency of contraction of the bladder after each route of administration. This effect lasted 1-3 hr and was not seen 24 hr later. Systemic administration of naloxone (10 mg/kg, i.v) also increased the frequency of bladder contraction and attenuated or abolished the effect of DAGO given intraventricularly or intrathecally and the delta-receptor agonist [2-D-penicillamine, 5-L-penicillamine] enkephaline (DPLPE).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Mu and delta opioid ligands inhibit reflex contractions of the urinary bladder in the rat by different central mechanisms.

The supraspinal and spinal mechanisms of opioid-induced inhibition of reflex contractions of the urinary bladder were studied in female rats, anesthetized with urethane. A variety of central manipulations was made to distinguish the effects produced by [D-Ala2-Me-Phe4-Gly(ol)5]-enkephalin (DAGO), a selective mu-opioid receptor ligand, from those of the delta ligand [2-D-penicillamine, 5-L-penicillamine]-enkephalin (DPLPE), administered by either intracerebroventricular (i.c.v.) or by spinal intrathecal (i.t.) injection. The effect of intraventricular but not of intrathecal administration of DPLPE was abolished 4-5 hr after the systemic administration of reserpine (5 mg/kg, i.p.). Reserpine did not modify the actions of DAGO, given by either route. Pretreatment with 5,7-dihydroxytryptamine (5,7-DHT, 200 micrograms, i.c.v.) attenuated the effect of DPLPE given intraventricularly but not when given intrathecally, measured 7 days later. The effect produced by DPLPE given by either route was unchanged by pretreatment with 6-hydroxydopamine (6-OHDA, 150 micrograms i.c.v.). Neither 5,7-DHT nor 6-OHDA altered the effect of administrations of DAGO. The effect of DPLPE given intraventricularly was attenuated or abolished, in a dose-related and reversible manner, following the administration of naloxone or methysergide intrathecally but not by phentolamine, propranolol or atropine. The effect of DAGO given intraventricularly was antagonised by naloxone but not by any of the other antagonists. These observations suggested that the supraspinally- and spinally-mediated inhibition of reflex contractions of the urinary bladder produced by mu or delta receptor ligands can be dissociated. The supraspinal effect of DPLPE involved a descending serotoninergic, but not adrenergic pathway.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Supraspinal and spinal mechanisms in morphine-induced inhibition of reflex urinary bladder contractions in the rat.

The supraspinal and spinal mechanisms of morphine-induced inhibition of isometrically recorded reflex urinary bladder contractions were studied in rats anesthetized with urethan. Chronic intracerebroventricular administration of 5,7-dihydroxytryptamine (200 micrograms) or 6-hydroxydopamine (150 micrograms), to selectively deplete central serotoninergic and noradrenergic systems, attenuated the intracerebroventricular effect but not the intrathecal effect of morphine. The intracerebroventricular effect of morphine was reversibly attenuated or abolished by an intrathecal injection of the novel delta-receptor antagonist ICI 174,864 (N,N-diallyl-Tyr-Arb-Aib-Phe-Leu-OH: Aib = alpha-aminoisobutyric acid) (1-3 micrograms) and by intrathecal methysergide (4-10 micrograms), phentolamine (5-10 micrograms), and yohimbine (5-10 micrograms) but not by intrathecal propranolol (10 micrograms), atropine (8 micrograms) or saline (2 micrograms) administered at similar molar concentrations and volumes respectively. These observations support the hypothesis that supraspinal and spinal mechanisms involved in morphine-induced inhibition of reflex urinary bladder contractions can be dissociated. The supraspinal actions of morphine were mediated indirectly via descending 5-hydroxytryptamine and noradrenergic pathways which activated specific 5-hydroxytryptamine and alpha-adrenergic but not beta-adrenergic receptor in the spinal cord. In addition, supraspinal morphine indirectly activated a spinal opioid system which could be directly activated by intrathecal morphine. The similarities between these observations and studies of central pathways mediating nociception and opioid analgesia suggest that similar physiological mechanisms control certain somatic and visceral activity.

Animals↗
PubMed1986

Centrally administered beta-endorphin produces prolonged changes in delta-opioid ligand activity in vivo.

Spontaneous reflex bladder contractions were recorded isometrically in urethane anesthetized rats. Bladder contractions were depressed by intracerebroventricular injections of the mu-opioid receptor agonist [D-Ala2,MePhe4,Gly(ol)5]enkephalin (DAGO) and the delta-agonist [2D-penicillamine,5D-penicillamine]enkephalin (DPDPE) respectively. The effect of DPDPE was selectively antagonized by ICI 174,864 (N,N-diallyl-Tyr-Aib-Aib-Phe-Leu-OH; Aib = alpha-aminoisobutyric acid). However following the administration of beta-endorphin the antagonistic action of ICI 174,864 could no longer be observed. In addition ICI 174,864 exhibited agonistic activity following beta-endorphin and the effects of DPDPE were prolonged in a dose related manner by beta-endorphin. These observations suggest that beta-endorphin may produce complex changes in central delta-opioid receptor activity.

Animals↗
PubMed1986

Meptazinol: unusual in vivo opioid receptor activity at supraspinal and spinal sites.

Systemic (1-10 mg/kg, s.c.), intracerebroventricular (i.c.v. 20-80 micrograms) and spinal intrathecal (i.t., 5-20 micrograms) administration of meptazinol hydrochloride produced dose-related inhibition of reflex contractions of the urinary bladder, recorded isometrically in urethane-anesthetized rats. The effects of meptazinol were reversed by naloxone administered by the same route. Indeed, this was achieved with intracerebroventricular or intrathecal administration of naloxone (2 micrograms), which also selectively antagonized the mu-receptor ligand [D-Ala2, MePhe4, Gly(ol)5]enkephalin (DAGO). However ICI 174,864 (3 micrograms, i.c.v. or i.t.), a delta-opioid receptor antagonist, did not affect the actions of meptazinol given intracerebroventricularly or intrathecally though it consistently abolished the equieffective actions of a selective delta-receptor ligand (2-D-penicillamine, 5-L-penicillamine) enkephalin (DPLPE). Naloxonazine (5 micrograms, i.c.v. or i.t.), an irreversible mu 1-opioid receptor antagonist, produced prolonged antagonism of the effects of DPLPE and meptazinol. The effects of DPLPE partially or completely recovered by 24 hr, indicating that naloxonazine produced prolonged antagonism of delta-opioid receptors. The effects of maptazinol however only recovered after 72 hr, suggesting that antagonism by naloxonazine of this ligand was irreversible and was mediated through a unique opioid receptor interaction. Subthreshold doses of meptazinol (10 micrograms, i.c.v.; 3 micrograms, i.t.) consistently antagonized the effects of morphine given intracerebroventricularly or intrathecally but not the equieffective doses of DPLPE or DAGO. These observations suggest that meptazinol inhibited reflex contractions of the bladder by supraspinal and spinal mu-opioid receptor activation. Furthermore, its agonistic effect and its antagonistic actions were compatible with interactions at a subpopulation of opioid receptors, possibly mu 1-receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Opioid inhibition of reflex urinary bladder contractions: dissociation of supraspinal and spinal mechanisms.

The supraspinal and spinal mechanisms of morphine induced inhibition of reflex urinary bladder contractions were studied in the urethane anesthetized rat. The inhibition of bladder contractions by intracerebroventricular (i.c.v.) morphine was abolished by intrathecal (i.t.) naloxone. In addition systemic reserpine (3.5-5.0 mg/kg, i.p.) abolished the inhibitory effect of both systemic morphine and i.c.v. morphine but not that of i.t. morphine. These data support the involvement of separate supraspinal and spinal mechanisms in the effects of morphine on bladder motility. The supraspinal effect appeared to be mediated indirectly via a monoaminergic system whereas the spinal action was mediated independently of monoamines. However, both the indirect supraspinal and the direct spinal mechanism involved a spinal naloxone-sensitive process possibly an endogenous enkephalinergic system.

Animals↗
PubMed1985

The proenkephalin A fragment, peptide E: central processing and CNS activity in vivo.

The proenkephalin A derivative, peptide E, delayed gastrointestinal transit in mice and inhibited the micturition reflex in anesthetized rats after intracerebroventricular (i.c.v.) administration. BAM22P, BAM12P and [Met5]enkephalin, possible processing fragments of peptide E, were also compared in the two test systems. Of these peptides, peptide E and BAM 22P were found to have the greatest potency and activity. Studies in vitro of peptide E metabolism by enzyme homogenates of mouse brain using HPLC techniques revealed that peptide E is bound to the membrane homogenate avidly for an extended period of time. The total formation of BAM22P, BAM12P, [Met5]enkephalin and all other peptide fragments during a 40 min incubation period accounted for only 8% of the total peptide E added to the homogenates. Thus, peptide E, rather than one of its known metabolites, appears to be of primary importance in the initiation of CNS-mediated effects. Further, these effects are probably the result of mu-opioid receptor activation.

Animals↗
PubMed1985

Prolonged in vivo antagonism of central mu- and delta-opioid receptor activity by beta-funal trexamine.

beta-Funaltrexamine (beta-FNA) was tested in the spinal cord and supraspinally against inhibition of reflex bladder contractions produced in the anesthetized rat by the opioid-receptor selective agonists [D-Ala2, MePhe4, Gly (ol)5]enkephalin (DAGO, mu-agonist) and [D-Pen2, D-Pen5] enkephalin (DPDPE, delta-agonist). All agents were microinjected either intracerebroventricularly (i.c.v.) or intrathecally (i.t.). beta-FNA (1-8 micrograms) produced long-lasting antagonism of both DAGO and DPDPE. Complete recovery from its effects was only observed some 24-32 h later. Higher doses of beta-FNA (4 and 8 micrograms i.t.) produced short-lived agonistic activity though the selectivity of this was not determined. It was concluded that beta-FNA was a potent, long-lasting antagonist at central opioid receptors in vivo but was unselective for the mu and delta opioid receptor.

Animals↗
PubMed1985

The rat urinary bladder. A novel preparation for the investigation of central opioid activity in vivo.

A novel method, which utilized spontaneous, volume-induced contractions of the urinary bladder in the anesthetized rat, was developed to assess the central activity of substances with opioid properties. It was discovered that intracerebroventricular (i.c.v.) injections made directly into the lateral ventricle or intrathecal (i.t.) injections made into the spinal subarachnoid space inhibited bladder contractions in a dose-dependent manner. The methods for spinal and supraspinal drug administrations are described as is the estimation of the spread of drug as determined by i.c.v. and i.t. dye injections. The pharmacology of the i.c.v. and i.t. effects of opioids was determined by use of selective opioid agonists (mu-agonists: morphine, DAGO; delta-agonists: DADLE, DPDPE; kappa-agonist: U-50, 488H) and antagonists (mu-antagonist, naloxone; delta-antagonist, ICI 174,864). It was concluded that the i.c.v. and i.t. effects were mediated by mu- and delta-opioid receptors and not by kappa-receptors. A number of other agents such as pentobarbital, haloperidol, and desipramine also inhibited bladder activity following i.c.v. and i.t. administration, but their actions were insensitive to naloxone. This in vivo model was considered useful in the detection and evaluation of the central actions of substances with opioid properties.

Animals↗
PubMed1985

Central delta-opioid receptor interactions and the inhibition of reflex urinary bladder contractions in the rat.

The in vivo effects of a number of opioid agonists and antagonists were studied on the spontaneous reflex contractions of the urinary bladder recorded isometrically in the rat anesthetized with urethane. All substances were administered into the central nervous system by the intracereboventricular (i.c.v.) or spinal intrathecal (i.t.) route. The conformationally restricted enkephalin analogues [2-D-penicillamine, 5-L-cysteine] enkephalin (DPLCE), [2-D-penicillamine, 5-L-penicillamine] enkephalin (DPLPE) and [2-D-penicillamine, 5-D-penicillamine] enkephalin (DPDPE) produced dose-related inhibition of reflex bladder contractions when administered by the i.c.v. or i.t. route. Both the novel delta-opioid receptor antagonist ICI 154,129 (200-600 micrograms) [N,N-bisallyl-Tyr-Gly-Gly-Psi-(CH2S)-Phe-Leu-OH) and ICI 174,864 (1-3 micrograms) [N,N-dially-Tyr-Aib-Aib-Phe-Leu-OH: Aib = alpha-aminoisobutyric acid] attenuated or abolished the effects of DPLCE, DPLPE and DPDPE when administered by the i.c.v. or i.t. route. The antagonism observed was selective since the equipotent inhibition produced by the mu-opioid receptor agonist [D-Ala2, Me-Phe4, Gly(ol)5] enkephalin (DAGO) was unaffected. Overall, ICI 154,129 was considerably weaker than ICI 174,864 and both antagonists inhibited bladder activity at doses higher than those required to demonstrate delta-receptor antagonism. Further studies of the agonistic effect of ICI 174,864 showed that it was insensitive to low doses of naloxone (2 micrograms, i.c.v. or i.t.) but could be abolished by higher (10-15 micrograms) doses of naloxone. These observations suggested that the agonistic effect of ICI 174,864 was not mediated by mu-opioid receptor. beta-Endorphin (0.2-1.0 micrograms, i.c.v.) inhibited bladder contractions but following recovery from this effect, appeared to prevent the expression of delta-receptor antagonism by ICI 174,864. In addition a previously subthreshold dose of ICI 174,864 now exhibited marked agonistic activity. The inhibitory effect of a submaximal dose of DPDPE was also potentiated by beta-endorphin under these circumstances. These observations suggest that supra-spinal and spinal delta-opioid receptors are involved in the opioid-mediated inhibition of reflex bladder contractions in the rat. Moreover beta-endorphin may be important in regulating central delta-opioid receptors.

Animals↗