Acute effects of vitamin B6 and fixed combinations of vitamin B1, B6 and B12 on nociceptive activity evoked in the rat thalamus: dose-response relationship and combinations with morphine and paracetamol.

Nociceptive activity was elicited in neurones of the thalamus by supramaximal electrical stimulation of afferent C fibres in the sural nerve of rats under urethane anesthesia. The fixed combination of vitamin B1, B6, and B12 (Neurobion) as well as of vitamin B6 administered by i.p. injection dose-dependently reduced the evoked nociceptive activity. The ED50 of Neurobion is 4.6 ml/kg (at 100 min after injection) and that of vitamin B6 is 189 mg/kg (at 90 min after injection). The minimum effective doses of Neurobion and vitamin B6 are 0.5 ml/kg and 40 mg/kg, respectively. When Neurobion or vitamin B6 were given at their minimum effective doses, and the minimum effective doses of morphine (0.025 mg/kg) or paracetamol (5 mg/kg) were injected i.v. 80 min later, i.e., when the maximum effect of higher doses of Neurobion or vitamin B6 was about to develop, no supraadditive effect developed. It is concluded that the antinociceptive effect caused by a single injection of Neurobion is largely due to vitamin B6. Vitamin B12 may contribute to this effect, whereas vitamin B1 alone exhibited only a slight effect on nociception. Moreover, it appears that Neurobion produces its antinociceptive effect after a single injection and after repeated administration during several days by different mechanisms so that the effect of analgesic agents is not enhanced following a single injection of Neurobion but may be enhanced after repeated administration of the compound.

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.

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.

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.

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.

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.

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.

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.