Antinociceptive properties of pyridoxine. Neurophysiological and behavioral findings.
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Analgesia↗
Biomedical subjects
I Jurna
Publications and source records attributed to I Jurna.
[Origin and conduction of pain in birth, effect of pain and analgesia on the mother, the birth process and fetus].
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Analgesia, Obstetrical↗
Flupirtine depresses nociceptive activity evoked in rat thalamus.
Flupirtine, a novel analgesic agent, was tested on nociceptive activity in neurones of the dorsomedial part of the ventral nucleus of the thalamus (VDM) and ascending axons of the spinal cord of rats under urethane anaesthesia. Activity was elicited by supramaximal stimulation of the sural nerve. Flupirtine injected i.v. dose dependently reduced nociceptive activity in the thalamus and ascending axons. The ED50 of flupirtine in depressing the thalamic response was 1.9 mg/kg, and the ED50 in depressing the C fibre-evoked response in ascending axons was 18 mg/kg. Naloxone reduced the depression of the nociceptive response evoked in the thalamus when applied before but not when applied after flupirtine. The results indicate that flupirtine produces analgesia by spinal inhibition of nociceptive impulse transmission from afferent nerve fibres to neurones sending their axons to the brain and, in addition, by supraspinal inhibition of nociceptive impulse transmission to the thalamus. Opioid mechanisms could be involved in these effects.
Afferent Pathways↗
Depression by flupirtine, a novel analgesic agent, of motor and sensory responses of the nociceptive system in the rat spinal cord.
The analgesic agent, flupirtine, was tested on motor and sensory responses of the nociceptive system in rats. The motor response was determined in the tail-flick test with radiant heat. The sensory response was determined as activity evoked in ascending axons by electrical stimulation of nociceptive afferents in the sural nerve. The tail-flick latency was dose dependently increased by flupirtine administered by intraperitoneal (i.p.) injection (ED50 7.8 mg/kg), intrathecal (i.t.) injection (ED50 14.8 micrograms/rat) or bilateral microinjection into the periaqueductal grey (PAG; ED50 2.6 micrograms/rat). Naloxone reduced the effect of an i.p. injection of flupirtine but was ineffective against an i.t. injection of the drug. The activity in ascending axons responding to afferent C fibre stimulation was depressed by flupirtine administered by intravenous (i.v.) injection (7 mg/kg) under urethane anaesthesia with an intact spinal cord and brain, and by i.t. injection (14 micrograms/rat) to decerebrated spinal rats. Naloxone did not abolish the depressant effect of i.t. injections of flupirtine. Microinjection of flupirtine (1.7 micrograms/rat) made in the PAG did not reduce, but increased the spontaneous and C fibre-evoked activity in ascending axons. The results indicate that flupirtine selectively depresses responses of the nociceptive system by a spinal (motor and sensory responses) and a supraspinal (motor response) action in which opiate-like mechanisms play no or a minor role.
Aminopyridines↗
Effects of tramadol on motor and sensory responses of the spinal nociceptive system in the rat.
The analgesic agent, tramadol, was tested on motor and sensory responses of the nociceptive system in rats. The tail-flick response to radiant heat was dose dependently depressed by tramadol (1-10 mg/kg i.p.), and the antinociceptive effect of the drug was reduced by naloxone in the same range of doses that antagonized the effect of morphine. Tramadol (100 micrograms) microinjected into the periaqueductal grey (PAG) prolonged the tail-flick latency and this effect was abolished by naloxone (0.2 mg/kg i.p.). Aminophylline (25 mg/kg i.p.) did not prevent the antinociceptive effect of tramadol (5 mg/kg i.p.). Tramadol (20 and 40 mg/kg injected i.v.; 100 and 200 micrograms injected intrathecally (i.t.); 100 micrograms injected into the PAG) depressed both the spontaneous activity in ascending axons and their activity due to stimulation of afferent C fibres and co-activation from afferent A delta fibres in the sural nerve. Naloxone injected i.v. at a dose (0.2 mg/kg) that had proven fully effective against the effects of morphine antagonized only the effect on spontaneous activity caused by i.v. injection of tramadol. A high dose of naloxone (1 mg/kg i.v.) not only abolished the depression of spontaneous activity caused by an i.t. injection of tramadol (200 micrograms) but also significantly reduced (but did not abolish) the activity in ascending axons evoked from afferent C fibres while the depression of co-activation from afferent A delta fibres remained unchanged. Aminophylline (50 micrograms i.t.) failed to abolish the depression by tramadol of ascending nociceptive activity. The activity elicited in ascending axons by stimulation of afferent A beta fibres was not changed by i.t. injection of tramadol (200 micrograms), which was evidence that the antinociceptive effect of tramadol is not due to a local anaesthetic action. It is concluded that tramadol produces its antinociceptive and analgesic effects through spinal and supraspinal sites of action. Since the effects of tramadol and morphine differ in some respects, it must be assumed that they are due to binding to different opiate receptors or that some of the effects of tramadol are not mediated by opiate receptors alone.
Animals↗
Central analgesic effect of paracetamol manifested by depression of nociceptive activity in thalamic neurones of the rat.
To study the question whether or not paracetamol produces a central analgesic effect, experiments were carried out on rats under urethane anaesthesia in which activity was elicited by supramaximal electrical stimulation of nociceptive afferents in the sural nerve and recorded from single neurones in the dorsomedial part of the ventral nucleus (VDM) of the thalamus. Paracetamol administered by intraperitoneal (i.p.) injection at doses of 50, 100 and 150 mg/kg reduced nociceptive evoked but not spontaneous activity. The amount of depression caused by the 3 doses and the time course of their effects was practically the same. suggesting that paracetamol is not capable to abolish nociceptive evoked activity in the thalamus but causes a maximum depression of the activity amounting to not more than about 60% of the controls. An intravenous (i.v.) injection of naloxone (1 mg/kg) did not diminish paracetamol-induced depression. The results present evidence for a central analgesic effect of paracetamol that is independent of endogenous opioids.
Acetaminophen↗
Mutual potentiation of antinociceptive effects of morphine and clonidine on motor and sensory responses in rat spinal cord.
Clonidine and morphine depress nociceptive reflex responses when given alone; when given in combination, the effect of each is potentiated by the other. The present study was designed to test if activity in ascending axons evoked by electrical stimulation of afferent C-fibers in the sural nerve of the rat also exhibits potentiation of the depressant effects of clonidine and morphine when both drugs are administered in combination by intrathecal (i.t.) injection to the lumbar spinal cord. For comparison, experiments were also carried out on the tail-flick response in rats. The results show that clonidine produced a dose-dependent inhibition of the tail-flick response (Ed50 20 micrograms); a combination of ineffective doses of clonidine (0.3 microgram) and morphine (2 micrograms) significantly inhibited the tail-flick response; clonidine (35 micrograms) reduced spontaneous, C-fiber-evoked and, due to co-activation, A delta-fibre-evoked activity in ascending axons; and clonidine at a threshold (0.3 microgram) or higher (3 micrograms) dose administered together with morphine at a dose (2 micrograms) that caused only a moderate inhibition produced a supra-additive effect in significantly depressing spontaneous. A delta- and C-fiber-evoked ascending activity. The dose-response curve of depression by morphine alone of C-fiber-evoked activity (ED50 8 micrograms) is significantly shifted by clonidine to the left (ED50 0.9 microgram). Naloxone (0.2 mg/kg) injected intravenously did not affect the inhibition of ascending activity caused by clonidine at the highest dose (35 micrograms), but it reduced the depressant effect of combined i.t. administration of clonidine and morphine. The potentiation of the antinociceptive effects of clonidine and morphine given in combination are possibly due to actions of the two drugs at different sites between the nociceptive afferents and the neurons sending their axons to the brain.
Afferent Pathways↗
The role of descending inhibition in the antinociceptive effects of the pyrazolone derivatives, metamizol (dipyrone) and aminophenazone ("Pyramidon").
The study was carried out to provide further evidence that the two pyrazolone derivatives, metamizol and aminophenazone, produce central antinociceptive effects by stimulating inhibition descending from the periaqueductal grey (PAG) to the spinal cord. Experiments were carried out on rats in which the tail-flick response to radiant heat, nociceptive activity in ascending axons of the spinal cord, and activity of neurones in the PAG and the substantia nigra were studied. Microinjection of procaine (10 micrograms) into the PAG reduced the tail-flick latency and abolished the increase in latency caused by i.p. injection of metamizol (40 mg/kg) and aminophenazone (150 mg/kg); it did not significantly reduce the antinociceptive effect of i.p. injection of morphine (2 mg/kg). Threshold doses of morphine (1 and 2 micrograms) administered by intrathecal (i.t.) injection potentiated the effect of threshold doses of metamizol injected i.p. (10 mg/kg) or into the PAG (10 micrograms) in the tail-flick test. Morphine (2 micrograms) injected i.t. potentiated the effect of i.v. injection of metamizol (80 mg/kg) on nociceptive activity in ascending axons by eliminating the stimulant effect of metamizol on about one third of the axons. Threshold doses of morphine injected i.t. failed to potentiate the antinociceptive effect of aminophenazone (50 mg/kg) injected i.p. in the tail-flick test. The results support the view that metamizol and aminophenazone activate pathways descending from the PAG and exerting an inhibitory effect on nociceptive impulse transmission at the spinal level.
Aminopyrine↗
Interaction of pentobarbital and morphine in the tail-flick test performed on rats: synergism at the spinal and antagonism at the supraspinal level.
The dose-dependence of the effects and interaction of pentobarbital and morphine administered by intrathecal (i.t.) and intraperitoneal (i.p.) injection was determined in experiments performed on the tail-flick response to radiant heat applied to the tail of rats. I.t. injection of pentobarbital and morphine, and i.p. injection of morphine depressed the tail-flick response, while i.p. injection of pentobarbital facilitated it. The effects caused by i.t. injection of the two drugs depended on the intensity of noxious stimulation. When pentobarbital and morphine were administered in combination by i.t. injection, they potentiated each other's effect. After i.p. injection of pentobarbital and morphine the facilitatory effect of pentobarbital was abolished and the antinociceptive effect of morphine was enhanced. The results reveal a synergism of the actions of pentobarbital and morphine at the spinal level and an antagonism at the supraspinal level which is probably of the functional type.
Animals↗
Morphological changes of rat neurosecretory neurones after stereotaxic injection of kainic acid into the supraoptic nucleus or the supraoptico-hypophyseal tract.
Kainic acid is a structural analogue of glutamic acid possessing neurotoxic property. In the present study, performed on rats, morphological changes of neurosecretory neurones after stereotaxic injection of kainic acid into the left supraoptic nucleus or into the left supraoptico-hypophyseal tract were investigated. It is shown that administration of kainic acid in a dose that leads to destruction of hippocampal pyramidal cells has no effects on supraoptic perikarya but does destroy neurosecretory axons. These results contradict the observations of many authors who reported that local injection of kainic acid into the brain causes degeneration of perikarya but leaves axons of passage unaffected.
Animals↗
Intrathecal injection of codeine, buprenorphine, tilidine, tramadol and nefopam depresses the tail-flick response in rats.
The effect of intrathecal (i.t.) injection of the analgesic agents, codeine, buprenorphine, tilidine and one of its metabolites, nortilidine, tramadol and nefopam, was determined in the tail-flick test performed on rats. ED50 values were derived from the dose-response lines. The relative potency ranking established from the ED50 values is buprenorphine (0.4 nM) greater than nortilidine (29 nM) = tramadol (26 nM) = nefopam (34 nM) greater than codeine (42 nM) greater than tilidine (118 nM). An i.t. injection of the opiate antagonist, naloxone (5 micrograms), prevented the antinociceptive effect of all analgesic agents administered at the highest dose tested. It is concluded that these analgesic agents, like morphine, exert their effect at least in part through a spinal site of action.
Analgesics↗
The effect of metamizol on the activity in the motor and sensory part of the nociceptive system in the rat spinal cord.
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Afferent Pathways↗
Effects of urapidil, clonidine, prazosin and propranolol on autonomic nerve activity, blood pressure and heart rate in anaesthetized rats and cats.
The influence of urapidil, clonidine, prazosin and propranolol on autonomic nerve activity was determined in anaesthetized cats and rats. The effects of these drugs on blood pressure and heart rate were also evaluated. Impulse output was recorded in the splanchnic and vagus nerve of the cat, and in the cervical sympathetic trunk of the rat. Urapidil increased activity in sympathetic and parasympathetic nerve fibres in cats at low doses without affecting blood pressure and heart rate. At higher doses which lowered blood pressure, urapidil reduced sympathetic impulse output in cats and rats while vagal output was increased. The alpha 1-adrenoceptor blocking agent, prazosin, did not affect activity in sympathetic and parasympathetic nerve fibres while the beta-adrenoceptor blocking agent, propranolol, increased activity in these nerves in cats. The alpha-adrenoceptor agonist, clonidine, reduced sympathetic impulse output at all doses tested in both rats and cats. The results provide evidence that urapidil, in addition to its peripheral alpha- and beta-adrenoceptor blocking properties, affects cardiovascular regulation by a central action. Blockade of alpha- or beta-adrenoceptors in the brain is probably not responsible for the central effect of urapidil.
Anesthesia↗
Depression by morphine and levorphanol of activity in sympathetic nerve fibres in anaesthetized rats.
In urethane-anesthetized rats, the effects of intravenous injections of morphine, levorphanol, dextrorphan, pentazocine and naloxone were studied studied on the activity in nerve fibres of the cervical sympathetic trunk, and on mean arterial blood pressure and heart rate. Impulse frequency in sympathetic nerve fibres was recorded with tungsten microelectrodes and proved to be more sensitive to drug action than blood pressure or heart rate. Morphine 1 and 2 mg/kg dose dependently reduced sympathetic impulse frequency, blood pressure and heart rate; morphine 0.5 mg/kg was ineffective. Levorphanol 1 and 2 mg/kg dose dependently reduced sympathetic impulse frequency and blood pressure but did not affect heart rate. Dextrorphan (the dextro-isomer of levorphanol) 2 and 4 mg/kg had no effect on the parameters tested. Pentazocine 3 and 6 mg/kg did not cause a consistent change in sympathetic impulse frequency, blood pressure and heart rate. Naloxone 0.2 mg/kg abolished the depressant effects of morphine and levorphanol and, when given alone, increased sympathetic impulse frequency. Naloxone 1 mg/kg increased blood pressure but did not affect heart rate. It is concluded that morphine can reduce blood pressure and heart rate by causing opiate-specific central sympathetic depression.
Adrenergic Fibers↗
Cyclic nucleotides and aminophylline produce different effects on nociceptive motor and sensory responses in the rat spinal cord.
The effect of intrathecal (i.t.) and systemic (i.p. and i.v.) administration of morphine, aminophylline, dibutyryl cyclic adenosine monophosphate (DBcAMP) and dibutyryl cyclic guanosine monophosphate (DBcGMP) on motor and sensory responses of the spinal nociceptive system was studied in rats. Motor responses were assessed in the tail-flick test performed on rats with an intact spinal cord, or as flexor reflex activity elicited in the electromyogram of the tibialis anterior muscle by supramaximal electrical stimulation of the sural nerve in rats in which the spinal cord was transected at the lower thoracic level. The sensory response consisted of activity in single ascending axons of the spinal cord evoked by electrical stimulation of afferent C fibres in spinal rats. Morphine (20 micrograms i.t. or 2 mg/kg i.p.) prolonged the tail-flick latency and aminophylline (25 mg/kg i.p. or 50 micrograms i.t.) prevented the antinociceptive effect of morphine. Aminophylline alone, administered by i.t. injection, reduced the tail-flick latency in a dose-dependent way. Morphine (2 mg/kg i.v. or 10 micrograms i.t.) reduced flexor reflex activity, and this reduction was abolished by aminophylline (25 mg/kg i.v. or 50 micrograms i.t.). Morphine (2 mg/kg i.v.) depressed spontaneous and evoked activity in single ascending axons responding to stimulation of afferent C fibres. This depressant effect of morphine was not abolished by aminophylline (50 micrograms i.t.); the depression was antagonized by naloxone (10 micrograms i.t.). DBcAMP (5 to 100 ng i.t.) dose-dependently prolonged the tail-flick latency. The antinociceptive effect of DBcAMP (50 ng i.t.) was prevented by aminophylline (50 micrograms i.t.) or naloxone (5 micrograms i.t.).(ABSTRACT TRUNCATED AT 250 WORDS)
Aminophylline↗
Depression of nociceptive sensory activity in the rat spinal cord due to the intrathecal administration of drugs: effect of diazepam.
The intrathecal (i.t.) administration of morphine inhibits nociceptive motor responses and activity in ascending axons evoked by stimulation of nociceptive afferent nerve fibers (nociceptive sensory response) in the rat. The i.t. administration of cholecystokinin octapeptide and ceruletide inhibits nociceptive motor responses, but does not affect ascending nociceptive activity. This shows that drug-induced depression of nociceptive motor responses is not always associated with depression of the nociceptive sensory response of the spinal cord. The microiontophoretic application of substance P excites single dorsal horn neurons that respond to noxious stimulation, whereas the i.t. administration of substance P inhibits both nociceptive motor and sensory responses. Thus, the results obtained from the i.t. administration of a drug may differ from those obtained from its application to single spinal neurons. Diazepam inhibits spinal reflexes and may reduce pain sensation in humans. To assess whether a spinal action is involved in the pain-relieving effect of diazepam, experiments were carried out on spinalized rats in which activity evoked by the stimulation of nociceptive and nonnociceptive afferent nerve fibers of the sural nerve was recorded from single ascending axons below the site of spinal cord transection. Diazepam, 20 micrograms i.t., reduced activity evoked by afferent A delta and C fiber stimulation and by stimulation of afferent A beta fibers. The depressant effect caused by diazepam, 2 mg/kg i.v., on C fiber-evoked ascending activity was reduced by the i.t. injection of the benzodiazepine antagonist, Ro 15-1788 (40 micrograms), an imidazodiazepine. It is concluded that the depression by diazepam of C fiber-evoked ascending activity contributes to pain relief caused by the drug.
Afferent Pathways↗
Pain-depressing agents and the spinal nociceptive system.
The spinal nociceptive system is the target of various pain depressing agents. It is capable to function without control from the brain. It is activated by tissue damage which, by excitation of nociceptive afferents, evokes activity in axons ascending to the brain (sensory nociceptive response) and in spinal reflex pathways (motor and autonomic responses). The prototype of an analgesic agent, morphine, suppresses nociceptive responses by binding to opiate receptors; it imitates the effect of the transmitter(s) released from endorphinergic neurones. Pentobarbital and diazepam reduce nociceptive (and non-nociceptive) responses by acting on the GABA receptor complex; both drugs facilitate the effect of the transmitter GABA which mediates presynaptic inhibition in the spinal cord. Pentobarbital may produce its effects by an additional action on postsynaptic neurone membranes. Clonidine depresses nociceptive responses, probably by imitating the action of the inhibitory transmitter, noradrenaline. Substance P acts as a "synaptic modulator"; it may facilitate or inhibit nociceptive responses. Ceruletide and cholecystokinin octapeptide depress nociceptive motor responses but do not affect the nociceptive sensory response. This indicates that motor and sensory responses of the spinal nociceptive system are not rigidly linked together. With the help of appropriate drugs, it is possible to manipulate them separately.
Analgesics↗
Intrathecal apamin selectively facilitates activity in ascending axons of rat spinal cord evoked by stimulation of afferent C fibers in sural nerve.
Intrathecally administered apamin was tested for its effect on activity in ascending axons of the spinal cord using decerebrate rats with low spinal cord transection. Afferent A beta, A delta or C fibers were stimulated in the sural nerve, and the response evoked in ascending axons was recorded below the transection. Apamin (5 ng) produced an increase in C fiber-evoked activity which developed about 30 min after injection and persisted for more than 60 min after injection. Apamin (5, 20 and 50 ng) did not change the activity in ascending axons which responded only to stimulation of afferent A beta and A delta fibers. The results indicate that apamin facilitates synaptic transmission from high-threshold afferent C fibers to secondary neurons.
Afferent Pathways↗