Effects of S 38093, an antagonist/inverse agonist of histamine H3 receptors, in models of neuropathic pain in rats.

BACKGROUND: Histamine H3 receptors are mainly expressed on CNS neurons, particularly along the nociceptive pathways. The potential involvement of these receptors in pain processing has been suggested using H3 receptor inverse agonists. METHODS: The antinociceptive effect of S 38093, a novel inverse agonist of H3 receptors, has been evaluated in several neuropathic pain models in rat and compared with those of gabapentin and pregabalin. RESULTS: While S 38093 did not change vocalization thresholds to paw pressure in healthy rats, it exhibited a significant antihyperalgesic effect in the Streptozocin-induced diabetic (STZ) neuropathy model after acute and chronic administration and, in the chronic constriction injury (CCI) model only after chronic administration, submitted to the paw-pressure test. Acute S 38093 administration at all doses tested displayed a significant cold antiallodynic effect in a model of acute or repeated administration of oxaliplatin-induced neuropathy submitted to cold tail immersion, cold allodynia being the main side effect of oxaliplatin in patients. The effect of S 38093 increased following chronic administration (i.e. twice a day during 5 days) in the CCI and STZ models except in the oxaliplatin models where its effect was already maximal from the first administration The kinetics and size of effect of S 38093 were similar to gabapentin and/or pregabalin. Finally, the antinociceptive effect of S 38093 could be partially mediated by α2 adrenoreceptors desensitization in the locus coeruleus. CONCLUSIONS: These results highlight the interest of S 38093 to relieve neuropathic pain and warrant clinical trials especially in chemotherapeutic agent-induced neuropathic pain. SIGNIFICANCE: S 38093, a new H3 antagonist/inverse agonist, displays antiallodynic and antihyperalgesic effect in neuropathic pain, especially in oxaliplatin-induced neuropathy after chronic administration. This effect of S 38093 in neuropathic pain could be partly mediated by α2 receptors desensitization in the locus coeruleus.

Evidence for an involvement of supraspinal delta- and spinal mu-opioid receptors in the antihyperalgesic effect of chronically administered clomipramine in mononeuropathic rats.

The mechanisms of involvement of the opioidergic system in the antinociceptive effect of antidepressants remain to be elucidated. The present study was designed to determine what type of opioid receptors may be involved at the spinal and supraspinal levels in the antihyperalgesic effect of clomipramine, a tricyclic antidepressant commonly prescribed in the treatment of neuropathic pain. Its antihyperalgesic effect on mechanical hyperalgesia (paw pressure test) in rats induced by chronic constriction injury of the sciatic nerve was assessed after repeated administrations (five injections every half-life, a regimen close to clinical use). Naloxone administered at a dose of 1 mg/kg i.v., which blocks all opioid receptors, or at a low dose of 1 microg/kg i.v., which selectively blocks the mu-opioid receptor, inhibited the anti-hyperalgesic effect of clomipramine and hence indicated that mu-opioid receptor is involved. Depending on whether they are administered by the intracerebroventricular or intrathecal route, specific antagonists of the various opioid receptor subtypes [D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-ThrNH2 (CTOP), mu; naltrindole (NTI), delta; and nor-binaltorphimine (nor-BNI), kappa] differently modify the antihyperalgesic effect of chronically injected clomipramine. The effect was inhibited by intrathecal administration of CTOP and intracerebroventricular administration of naltrindole, whereas nor-BNI was ineffective whatever the route of injection. These results demonstrate a differential involvement of opioid receptors according to the level of the central nervous system: delta-receptors at the supraspinal level and mu-receptors at the spinal level. Clomipramine could act via a neuronal pathway in which these two receptors are needed.

Effects of quinidine, verapamil, nifedipine and ouabain on hysteresis in atrial refractoriness in the conscious dog: an approach to ionic mechanisms.

1. This work determines the effects of quinidine, verapamil, nifedipine and ouabain on the hysteresis of the atrial effective refractory period (AERP) in the conscious dog. 2. AERP was always longer in the increasing phase than in the decreasing phase of the extrastimulus method, thus demonstrating the existence of AERP hysteresis. Calculated as the difference between the two values, hysteresis was between 8+/-0.8 and 11+/-1.0 msec. 3. Quinidine increased hysteresis from 9+/-0.7 to 13+/-0.7 msec, whereas verapamil decreased it from 10+/-0.9 to 5+/-0.5 msec and nifedipine did not affect it. Ouabain also lengthened hysteresis from 8+/-0.8 to 11+/-1.2 msec. 4. Thus, these results confirm the existence of a hysteresis phenomenon in the AERP in the conscious dog and are evidence that the fast sodium and slow calcium specific membrane currents participate in this phenomenon.

Effect of analgesics on audible and ultrasonic pain-induced vocalization in the rat.

Brief electrical pulses applied to the rat tail elicit a complex vocal response which includes audible (peeps, chatters) and ultrasonic (USV) components. Aspirin and amitriptyline had no effect on the vocal responses. Morphine showed a dose-dependent and naloxone reversible antinociceptive effect on the 1st and 2nd audible peeps by decreasing their intensity (evaluated by their envelopes which correspond to the outer bounds of the soundwave amplitude plotted as a function of time), with ED50 values of 1.96 mg/kg and 0.36 mg/kg i.v. respectively. Paracetamol significantly reduced only the intensity of the second peep at the dose of 200 mg/kg iv. Chatter intensity was decreased by doses of 1 and 3 mg/kg i.v. of morphine which would suggest an effect on emotional components of pain. The intensity of USV was affected by morphine injection although the variations observed were non-significant. These data clearly implicate a specific role for the opioid analgesics in modifying the vocal pain related behaviors.

Audible and ultrasonic vocalization elicited by a nociceptive stimulus in rat: relationship with respiration.

Brief electrical pulses applied to a rat's tail elicit complex vocal responses including audible ("peeps," "chatters") and ultrasonic components. These responses, particularly the two first peeps which have been shown to be triggered by A delta- and C-fibers, could provide a useful tool in pain studies. In the present study, we aimed to optimize this test by investigating the influence of respiration on the vocal responses. The following results were obtained: 1) As expected, the vocalization periods were concomitant with expiration; 2) The phase of the respiratory cycle at the onset of stimulation did not modify the mean intensities of the peeps; 3) The lung volume at the onset of stimulation significantly influenced the intensity and duration of the first peep and the latency of the second peep. Taking account of respiratory parameters in pain tests based on a quantified analysis of vocal responses could improve their sensibility by reducing variability and their specificity by detecting confounding factors such as effects of drugs on respiratory centres or on motor function.

Cardiac vagal effects of rilmenidine in the dog: comparison with clonidine.

1. The cardiac vagal effects of rilmenidine (5 micrograms kg-1 min-1) and clonidine (0.5 micrograms kg-1 min-1) were studied in chloralose anaesthetized dogs. 2. Rilmenidine and clonidine progressively reduced the vagal stimulation-induced bradycardia. As indicated by the ED70, rilmenidine was about 23 times less potent than clonidine in this respect. Concomitantly, both drugs dose-relatedly decreased heart rate and mean blood pressure with potency ratios of rilmenidne to clonidine of about 1:23 and 1:12, respectively. 3. Importantly, the heart rate values observed under vagal stimulation during drug infusion never exceeded the values under basal vagal stimulation, and with both drugs large interindividual variations occurred under vagal stimulation. 4. These results show that the vagal bradycardia inhibition produced by rilmenidine and clonidine results from their true bradycardic effects and not from actual cardiac vagolytic properties.

Hysteresis in atrial refractoriness in the conscious dog: influence of stimulation parameters and control by the autonomic nervous system.

This work (a) provides evidence for hysteresis in the atrial effective refractory period (AERP) in the conscious dog; (b) studies the main stimulation parameters that may affect this phenomenon; and (c) evaluates the influence of the autonomic nervous system. AERP was measured by the extrastimulus method in the conscious dog with chronic atrioventricular block (n = 6) during the increasing and decreasing phases of an S1S2 fixed protocol. AERP was longer during the increasing phase than during the decreasing phase, thus demonstrating hysteresis, calculated as the difference between the two values. Hysteresis was greater with an S1S1 basic cycle length of 300 ms than with a basic cycle length of 400 ms, 9 +/- 0.9, and 7 +/- 0.9 ms, respectively. It was also greater with trains of six basic cycles before each extrastimulus S2 than with trains of 12 basic cycles, 9 +/- 0.9 and 7 +/- 1.0 ms, respectively. Suppression of vagal tone with atropine reduced hysteresis from 8 +/- 0.6 to 4 +/- 0.6 ms, whereas suppression of cardioaccelerator tone with propranolol increased it from 9 +/- 0.9 to 14 +/- 1.2 ms. These data were confirmed by the neostigmine-induced increase in hysteresis from 8 +/- 0.8 to 11 +/- 0.8 ms and the isoproterenol-induced decrease in hysteresis from 9 +/- 0.6 to 4 +/- 0.4 ms. Overall, these results provide evidence for a hysteresis effect in the AERP in the conscious dog that is stimulation frequency-dependent and modulated by the autonomic nervous system with permanent increase by vagal tone and decrease by cardioaccelerator tone.

Cardiac electrophysiological effects of falipamil in the conscious dog: comparison with alinidine.

We studied the cardiac electrophysiological effects of falipamil, a specific bradycardic agent, in conscious dogs, in comparison with those of alinidine. Sinus rate, corrected sinus recovery time, and Wenckebach point were measured in six intact dogs. Atrial rate, ventricular rate, and atrial effective refractory period were measured in six atrioventricular-blocked dogs. In both groups, blood pressure was also monitored. Each dog received, with at least a three-day interval, falipamil (hydrochloride) and alinidine (hydrobromide) in four successive intravenous injections, 30 min apart, at 0.5, 0.5, 1, and 2 mg kg-1. Falipamil increased sinus rate and atrial rate, but decreased ventricular rate, whereas alinidine decreased sinus rate and ventricular rate, but increased atrial rate. Falipamil shortened corrected sinus recovery time and increased Wenckebach point, whereas alinidine lengthened corrected sinus recovery time and decreased Wenckebach point. Falipamil and alinidine increased atrial effective refractory period. Neither falipamil nor alinidine modified mean blood pressure in either group. Overall, these results show that (a) falipamil exhibits effects on the electrical activity of the heart, reflecting the predominant direct vagolytic effect of this drug, (b) alinidine exhibits effects reflecting the marked antiarrhythmic potential of this agent, and (c) thus indicate that two drugs with almost identical specific bradycardic properties can produce quite different electrophysiological effects in the conscious dog.

Interactions of the cardiac chronotropic effects of rilmenidine with the autonomic nervous system in conscious dogs: comparison with clonidine.

1. The cardiac chronotropic effects of rilmenidine (10-100 micrograms kg-1) and clonidine (1-10 micrograms kg-1) were studied in conscious dogs with chronic atrioventricular block. 2. Rilmenidine and clonidine initially (< 3 min) decreased atrial rate, although the effect was not related to dose. More lastingly, ventricular rate was decreased in a dose-related manner (ratio, 1:21). Rilmenidine lowered mean blood pressure only at 100 micrograms kg-1, while clonidine had the same effect at doses of 5 micrograms kg-1 upward (ratio, 1:15). 3. When administered after atropine and pindolol, rilmenidine (50 micrograms kg-1) produced a decrease in atrial rate, with an identical intensity but longer duration than under basal conditions. When clonidine (2.5 micrograms kg-1) was given after atropine, no chronotropic atrial effect was observed. However, when clonidine (2.5 micrograms kg-1) was given after pindolol, it produced a decrease in atrial rate that was more marked, both in intensity and duration, than under basal conditions. After phenoxybenzamine, rilmenidine decreased atrial rate with a more marked and lasting effect than observed under basal conditions. Clonidine produced a bradycardic atrial effect identical to the basal effect. After yohimbine, rilmenidine and clonidine decreased atrial rate with an intensity similar to that under basal conditions, although the time course was totally different. 4. When given after atropine, rilmenidine (50 micrograms kg-1) and clonidine (2.5 micrograms kg-1) decreased ventricular rate as under basal conditions, whereas after pindolol and phenoxybenzamine, both drugs decreased ventricular rate less markedly than under basal conditions, both in intensity and duration. After yohimbine, rilmenidine and clonidine produced no chronotropic ventricular effect. 5. These results show that (a) the initial atrial bradycardia caused by rilmenidine results from both a decrease in sympathetic tone and an increase in cholinergic activity; while the effect of clonidine is caused mainly by the enhancement of cholinergic activity. For both drugs, alpha 2-adrenoceptors are involved at least in the initiation of the effect; (b) the very short duration of atrial bradycardia may result from reflex buffering in response to ventricular bradycardia. This buffering is less effective when heart rate was high; and (c) the ventricular bradycardia caused by both drugs is mainly the result of a decrease in sympathetic tone in response to the stimulation of alpha 2-adrenoceptors. The results also suggest that negative chronotropic postsynaptic alpha 2-adrenoceptors could be involved in the ventricular bradycardia.

Audible and ultrasonic vocalization elicited by single electrical nociceptive stimuli to the tail in the rat.

We describe audible and ultrasonic vocalization elicited in rats by a short electrical pulse applied to the tail. Three types of vocal emissions were recorded: (1) 'peep', characterized by a repartition of energy over a wide range (0-50 kHz) of frequencies without any clear structure; (2) 'chatters', characterized by an audible (frequencies in hearing range of humans) fundamental frequency (2.47 +/- 0.03 kHz) and harmonics; and (3) 'ultrasonic emissions', characterized by a succession of slightly modulated pulses with frequencies in the 20-35 kHz range. Peeps and chatters were never recorded before the application of the stimuli. Several different vocalization patterns were described in terms of these types of responses. Just after the stimulation, all the animals emitted a 1st peep, which was generally (61%) followed by a 2nd one. They appeared with reproducible latencies, durations and envelopes. The envelopes of the audible (peeps and chatters) responses were intensity-dependent. Experimental data (moving the stimulation site, lidocaine injection) indicated that the 1st and 2nd peeps were triggered by two different groups of peripheral fibres with mean conduction velocities of 7.3 +/- 0.8 and 0.7 +/- 0.1 m/sec, respectively. This suggested an involvement of A delta and C fibres. Morphine showed a naloxone-reversible and dose-dependent antinociceptive effect by decreasing the 1st and 2nd peep envelopes. It is concluded that a short stimulus applied to the tail triggers a complex behavioural repertoire. It is proposed that this model will be a useful tool for physiological and pharmacological studies of nociception.

Cardiac electrophysiologic effects of alinidine, a specific bradycardic agent, in the conscious dog: plasma concentration-response relations.

We studied the cardiac electrophysiologic effects of alinidine in conscious dogs. Sinus rate, corrected sinus recovery time (CSRT), and Wenckebach point (WP) were determined in 6 intact dogs. Atrial and ventricular rates, and atrial effective refractory period (AERP) were determined in 6 atrioventricular (AV)-blocked dogs. In both groups, we also measured blood pressure (BP) and plasma alinidine concentrations. Each dog received four intravenous (i.v.) injections of 0.5, 0.5, 1, and 2 mg/kg alinidine (hydrobromide) 30 min apart. At all doses, alinidine decreased sinus rate (< or = 43%) and ventricular rate (< or = 44%), but increased atrial rate (< or = 31%). It lengthened CSRT (< or = 71%) at the two highest doses and increased AERP (< or = 33%) and decreased WP (< or = 33%) at all doses. Alinidine did not modify mean BP at any dose in either group. Overall, these results indicate that alinidine exhibits electrophysiologic effects in conscious dogs that reflect antiarrhythmic potentials of this drug apart from its assumed antiischemic properties.

Chronotropic cardiac effects of NPY in conscious dogs: interactions with the autonomic nervous system and putative NPY receptors.

The chronotropic cardiac effects of neuropeptide Y (NPY) were studied in the conscious dog with chronic atrioventricular block. NPY (0.2-5 micrograms/kg i.v.) produced no effect on atrial cycle length (ACL), and increased ventricular cycle length (VCL) and mean arterial blood pressure (MBP). After atropine, NPY produced no effect on ACL and increased MBP. At 0.2 microgram/kg, it shortened VCL, whereas at 1 and 5 micrograms/kg, it lengthened this parameter. After pindolol, NPY produced no effect on ACL, shortened VCL and increased MBP. These results indicate that in the conscious dog, NPY (0.2-5 microgram/kg i.v.) does not exert any chronotropic effect on the sinoatrial node, most likely because of competition between opposite chronotropic effects and/or absence of specific NPY receptors in the sinoatrial node. They also suggest that the ventricular bradycardic effects produced by NPY result mainly from a reflex withdrawal of beta-adrenergic tone and that its ventricular tachycardic effects result from a direct action of NPY on specific receptors located in the His bundle.

Chronotropic cardiac effects of falipamil in conscious dogs: interactions with the autonomic nervous system and various ionic conductances.

The chronotropic cardiac effects of falipamil were studied in conscious dogs with chronic atrioventricular (AV) block. Falipamil (0.5-2 mg/kg) initially increased atrial rate dose dependently. After atropine and atropine-pindolol, falipamil (2 mg/kg) decreased atrial rate, but after pindolol, it did not modify atrial rate. After atropine-pindolol-phenoxybenzamine, atropine-pindolol-yohimbine, atropine-pindolol-verapamil, and atropine-pindolol-quinidine pretreatment, falipamil produced atrial bradycardia. Falipamil dose-relatedly decreased ventricular rate. Falipamil (2 mg/kg) decreased ventricular rate after atropine, pindolol, and atropine-pindolol more than under basal conditions. After the other four pretreatments, it also produced ventricular bradycardia. Falipamil did not affect mean blood pressure (MBP) at any dose. These results (a) show that the initial atrial cardio-acceleration produced by falipamil results from its direct vagolytic action; (b) show that absence of atrial bradycardia results from buffering by the vagolytic effect and/or a relatively low basal atrial rate; (c) suggest that the falipamil ventricular bradycardia is partly buffered by the vagolytic effect, norepinephrine (NE) release, and involvement of alpha 2-adrenoceptors; (d) exclude involvement of postsynaptic muscarinic, alpha- and beta-adrenoceptors, and of the slow calcium current in the mechanism(s) by which falipamil decreases cardiac automaticity; and (e) suggest possible involvement of a quinidine-sensitive current in this (these) mechanism(s).

Membrane stabilizing activity and beta-adrenoceptor antagonist-induced bradycardia in conscious dogs.

The atrial effective refractory period (AERP) and atrial and ventricular chronotropic effects of the stereoisomers of propranolol, pindolol, metoprolol and penbutolol were studied in conscious atrio-ventricular blocked dogs. Atrial beta-adrenoceptor blocking activity was assessed for all the drugs against isoprenaline. All the drugs except dextro-pindolol lengthened AERP and decreased ventricular rate dose relatedly. At comparable levels of atrial beta-adrenoceptor blockade, dextro-propranolol, dextro-metoprolol and dextro-penbutolol were more potent to induce AERP lengthening than their respective levo-isomers, whereas dextro-pindolol was less potent than levo-pindolol. In addition, levo-pindolol and levo-metoprolol were more potent to produce ventricular bradycardia than the corresponding dextro-isomers, whereas the levo- and dextro-isomers of propranolol and penbutolol were equipotent. These results confirm that the ventricular bradycardia induced by the different beta-adrenoceptor antagonists is partly due to ventricular beta-adrenoceptor blockade and to the membrane stabilizing activity of these drugs, and partly to another as yet unknown factor seen especially with the levo-isomers and particularly marked with metoprolol.

Mechanisms of chronotropic cardiac effects of alinidine and plasma concentration-response relationships in the conscious dog with chronic atrioventricular block.

The chronotropic cardiac effects of alinidine were studied in the conscious dog with chronic atrioventricular block. Alinidine at 0.5 - 4 mg/kg, i.e., at plasma concentrations between 42 +/- 2 and 1625 +/- 371 ng/ml, initially increased atrial rate dose-dependently. This effect fell off rapidly, but atrial bradycardia was never observed. After atropine and pindolol, which raised basal atrial rate, alinidine (2 mg/kg) decreased atrial rate, whereas after phenoxy-benzamine, yohimbine or phentolamine, it produced atrial effects identical to those observed under basal conditions, i.e., initial tachycardia and no bradycardia. Alinidine dose-relatedly decreased ventricular rate. None of the pretreatments modified the maximal ventricular bradycardia, but interestingly after pindolol or yohimbine this effect developed more rapidly (maximal bradycardia between 3 and 5 against 30 min) and then declined progressively. Alinidine did not modify mean blood pressure at any dose. After atropine, phenoxybenzamine or phentolamine, alinidine remained without effect on mean blood pressure, but after pindolol or yohimbine, a hypotensive effect appeared concomitantly with the reduction of the ventricular bradycardia. These results show that the initial atrial cardioacceleration due to alinidine results from a direct vagolytic action of this drug and that the absence of atrial bradycardia results from buffering by the vagolytic effect and/or a relatively low basal atrial rate. They also suggest that the ventricular bradycardia does not involve either the muscarinic cholinoceptors or the alpha- or beta-adrenoceptors, though the results obtained after pindolol or yohimbine suggest possible involvement of a fall in sympathetic tone by stimulation of presynaptic or central alpha2-adrenoceptors, particularly in the persistence of the bradycardic effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Study of histamine release induced by acute administration of antitumor agents in dogs.

The effects of eight antitumoral drugs known to cause anaphylactoid side effects in clinical use were studied in dogs. Blood pressure, heart rate, and blood and plasma histamine levels were monitored. L-asparaginase, methotrexate, 5-fluorouracil, bleomycin, and cisplatin had no effect on these parameters. Doxorubicin, Vehem (teniposide), and Vepeside (etoposide) induced hypotension, tachycardia, and a rise in histamine levels. In the cases of Vehem and Vepeside, the excipient (respectively, cremophor EL and tween 80) induced the same effects. These agents, like elliptinium, which had been previously studied, induce nonspecific histamine release--unlike the other drugs studied. The mechanism of clinically observed anaphylactoid side effects is discussed in the light of these findings.