Naloxone antagonizes theophylline-induced potentiation of morphine inhibition of a nociceptive reaction in rats.

In the rat, theophylline has been shown to potentiate the effect of morphine on the threshold for vocalisation after withdrawal of stimulation. This response to painful stimulation is considered to be integrated at the level of the thalamus-hypothalamus-rhinencephalon. Naloxone antagonized the effect of the combined treatment with morphine and theophylline, suggesting pharmacological specificity for morphine. Moreover, the theophylline-induced enhancement of this pharmacological response to morphine was attenuated after pimozide pretreatment, indicating an underlying dopaminergic mechanism.

Promethazine both facilitates and inhibits nociception in rats: effect of the testing procedure.

The present study demonstrates that low doses of promethazine (1.25-5 mg/kg SC) dose-dependently facilitate nociception in the vocalization test in rats. However, this effect disappeared gradually with increasing dose, and in contrast, high doses (20-40 mg/kg SC) induced an antinociceptive effect. This indicates that promethazine, depending upon the biophase concentration, has the potential to interact with separate antagonizing or opposing functional systems, producing contrasting effects on nociception. The sigmoid Emax model was fitted to the observed composite effect, and dose-response characteristics for two opposite effects were described. In addition, when suprathreshold stimulation was used to evoke nociception, the stimulus amplified the hyperalgesic efficacy of promethazine but left the potency of this effect unaltered. In this experimental situation only negligible antinociception was observed. Our data thus show that for promethazine, the net effect on nociception in rats is not absolute but is balanced both by the biophase concentration and by the effectiveness of the stimulation used to evoke nociception.

Antinociceptive action of oxotremorine and regional turnover of rat brain noradrenaline, dopamine and 5-HT.

In the rat, oxotremorine increases the threshold for vocalisation after-discharge (affective component of pain reactions) dose dependently at subtremor doses (30-67 mug/kg s.c.). Doses of 225-506 mug/kg were needed to elevate the thresholds for vocalisation and motor response. 1-Tryptophan, PCPA, alpha-methyl-p-tyrosine, 1-Dopa, pimozide and LSD-25 did not affect the antinociceptive activity of oxotremorine, while phenocybenzamine slightly increased the threshold for vocalisation. Oxotremorine did not change the endogenous brain concentrations of noradrenaline and dopamine or 5-HT but decreased that of 5-HIAA in all brain regions at the time of maximal analgesia. The decrease of 5-HIAA was still present after pretreatment with probenecid. After inhibition of tyrosine hydroxylase, oxotremorine accelerated the depletion of dopamine in telencephalic cortex during maximal antinociceptive activity and of noradrenaline in all brain regions at a time when this activity had vanished. Atropine significantly antagonized the analgesic activity of oxotremorine. It is concluded that oxotremorine antinociceptive activity in the rat is related to a cholinergic compoent, while a monoaminergic component is not directly involved.

Noradrenaline but not dopamine involved in NMDA receptor-mediated hyperalgesia induced by theophylline in awake rats.

Theophylline dose-dependently decreased a supraspinally integrated nociceptive threshold in awake rats. This hyperalgesia was antagonized by pretreatment with the N-methyl-D-aspartate (NMDA) receptor antagonist (+)-MK-801, suggesting involvement of NMDA receptors. Depletion of endogenous catecholamines with reserpine or alpha-methyl-DL-p-tyrosine and inhibition of noradrenaline synthesis with FLA 63 reduced the theophylline-induced hyperalgesia, whereas blockade of dopamine D2 receptors by pimozide, haloperidol (2 mg/kg) or (-)-sulpiride, of dopamine D1 receptors by SCH 23390, or of dopamine autoreceptors by a low dose of haloperidol (25 micrograms/kg), had no effect. By contrast, the alpha 1-adrenoceptor-blocking agent phenoxybenzamine abolished the hyperreactivity induced by theophylline, whereas the alpha 1-adrenoceptor antagonist prazosin and the beta-adrenoceptor antagonist (+/-)-propranolol were without effect. Furthermore, the alpha 2-adrenoceptor agonist clonidine (50 micrograms/kg) considerably decreased the hyperalgesia caused by theophylline. The adenosine A1/A2 receptor agonist N-ethyl-carboxamide adenosine (NECA) produced dose-dependent antinociception on the threshold for vocalization. Moreover, NECA (25 micrograms/kg) antagonized the hyperalgesia induced by different doses of theophylline, indicating that the effect is susceptible to purinergic modulation. It is suggested that theophylline-induced hyperreactivity to nociception is attributed to increased activity in NMDA and noradrenaline neurotransmission, possibly secondary to adenosine antagonism. Elevated intracellular levels of cyclic AMP might, however, also be involved in theophylline-produced hyperexcitability.

Evaluation of the antinociceptive effects of 4, alpha-dimethyl-m-tyramine (H 77/77) in the rat.

4, alpha-Dimethyl-m-tyramine (H 77/77) has been shown to induce dose dependently antinociceptive activity against 3 parameters: (1) the motor (M), (2) the vocalisation during stimulation (V) and (3) the vocalisation after withdrawal of stimulation (VA) responses. The effect of H 77/77 upon the V and VA pain responses was abolished or reduced by prior treatment with phenoxybenzamine, chlorpromazine, H 44/68, FLA 63, reserpine and protriptyline, and was potentiated by atropine sulphate. It is suggested that H 77/77 may exert is inhibitory effect on painful stimulation predominantly by inhibiting spinal sensory input.

Opposing effects of apomorphine on pain in rats. Evaluation of the dose-response curve.

The effect of apomorphine on a supraspinally mediated response to pain was studied after subcutaneous administration of 10 different doses (25 micrograms/kg up to 10 mg/kg). Depending on the dose given, apomorphine was found to induce opposing effects on pain, so that low doses, 25-100 micrograms/kg, dose-dependently increased the sensitivity to pain. This effect then gradually declined in potency with increasing doses and high doses induced antinociception. The data therefore suggest that the net effect recorded involves the sum of responses from at least two functional systems. Using the Hill equation and the digital computer program NONLIN, we have dissociated the observed effect into two components, each having its particular dose-response characteristics: low doses having an ED50 value of 36 micrograms/kg produced hyperreactivity to pain, and high doses having an ED50 of 465 micrograms/kg (in the absence of hyperalgesia) induced antinociception.

Development of tolerance to the analgesic effect of clonidine in rats. Cross-tolerance to morphine.

The influence of chronic treatment with clonidine on analgesia produced by clonidine and morphine was studied in rats. Electrical stimuli were applied to the tail, and analgesia was measured as increase in the threshold voltage that elicited vocalisation. Twenty-two hours after the last of 14 injections of increasing doses of clonidine over 7 days, the acute analgesic effects of both clonidine and morphine were reduced, i.e. tolerance had developed. Pretest vocalisation thresholds (voltage) were unchanged by long-term treatment with clonidine, or, respectively, saline. Contrarywise, acute administration of clonidine enhanced the effect of morphine. The tolerance developed after long-term treatment with clonidine might be associated with changes in brain noradrenaline mechanisms.

Clonidine antinociceptive activity: effects of drugs influencing central monoaminergic and cholinergic mechanisms in the rat.

Clonidine is able to increase the threshold for vocalisation during stimulation and the threshold for vocalisation after withdrawal of stimulus (vocalisation afterdischarge). These effects of clonidine were investigated after treatment of rats with drugs influencing central monoaminergic and cholinergic mechanisms. Chlorpromazine, atropine and p-chlorophenylalanine increased the activity of clonidine at both thresholds while phenoxybenzamine and reserpine pretreatment increased the activity at the thresholds for vocalisation only. Yohimbine decreased clonidine activity at both thresholds while 5-HTP and alpha-methyl-p-tyrosine decreased the effects at the threshold for vocalisation afterdischarge. Naloxone did not change the activity of clonidine at either pain response studied. It is concluded from the present findings that influence from several neuronal systems modulate the antinociceptive action of clonidine. The inhibition of the medullary nociceptive response after clonidine might be connected to a decreased activity of noradrenergic neurons. Endogenous noradrenaline seems to be of minor importance in mediating this effect. It is moreover shown that decreased cholinergic receptor activity enhances clonidine antinociceptive action on both medullary and diencephalic-rhinencephalic pain responses. The possible involvement of serotonin these functional responses after clonidine is also discussed.

Yohimbine both increases and decreases nociceptive thresholds in rats: evaluation of the dose-response relationship.

The effect of yohimbine on a response to nociceptive stimulation mediated by supraspinal structures was studied after subcutaneous administration in doses from 0.25 mg/kg up to 25 mg/kg. The results showed that to describe adequately the dose-response relationship of yohimbine in pain modulation, characteristics of opposing effects had to be considered: low doses with an ED50-value of 0.56 mg/kg were found to dose-dependently facilitate nociception whereas high doses instead induced antinociception with an ED50 of 4.74 mg/kg. The possible capacity of alpha 2-adrenoceptors to modulate responses to nociception is discussed.

Concentration-response relations for apomorphine effects on heart rate in conscious rats.

The pharmacokinetics of apomorphine in plasma and brain tissue have been studied in relation to the time courses of effects on heart rate in conscious rats. The kinetic behaviour was investigated after 2 mg kg-1 i.v. and 5 mg kg-1 s.c., respectively. Apomorphine showed a high total plasma clearance (165-207 ml min-1 kg-1) and, despite a relatively large volume of distribution (3.4-4.1 litre kg-1), a biological half-life of about 14 min was obtained irrespective of route of administration. The kinetics in whole brain were identical with those in plasma. Apomorphine produced biphasic effects on the heart rate during the time courses of subcutaneous single doses: a low dose (50 micrograms kg-1) induced pure bradycardia while the doses of 100 micrograms kg-1 and 5 mg kg-1 produced responses oscillating between bradycardia and tachycardia. When we evaluated the relation between apomorphine concentrations and effects on the heart frequency with a composed sigmoid Emax model, apomorphine exhibited a U-shaped steady-state plasma concentration-response curve. Bradycardia appeared after low concentrations, reached a maximum and then decreased with increasing concentrations. A further augmentation of apomorphine concentration resulted in the opposite effect, i.e. tachycardia. Separate concentration-response curves for bradycardia and tachycardia were calculated. The changes in biophase concentration that occur during the absorption and disposition may thus cause the fluctuations between contrasting effects seen during the time course of a single dose.

L-dopa induces opposing effects on pain in intact rats: (-)-sulpiride, SCH 23390 or alpha-methyl-DL-p-tyrosine methylester hydrochloride reveals profound hyperalgesia in large antinociceptive doses.

The present study shows that during the time course of the action of single doses, L-dopa induces multiphasic opposing effects on pain, recorded as vocalization during the presentation of electrical stimulation applied to the tail of normal rats. This indicates that two or more functional systems contribute to produce the net response. A small dose (15 mg/kg) of L-dopa facilitates pain slightly, whereas larger doses (100-200 mg/kg) can produce an antinociceptive effect following an initial hyperalgesia. Moreover, profound hyperalgesia is revealed by either dopamine (DA) D1 and D2 receptor blockade by means of SCH 23390 [R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetra-hydro-1H- 3-benzazepine hydrochloride] or (-)-sulpiride, respectively, as well as after a reduction of the presynaptic synthesis of catecholamines after pretreatment of the animals with the tyrosine hydroxylase inhibitor alpha-methyl-DL-p-tyrosine (alpha-MPT). The enhancement of L-dopa's hyperalgesic effect after SCH 23390 treatment is maximal already at the onset of the effects, whereas (-)-sulpiride or alpha-methyl-DL-p-tyrosine precipitates the hyperalgesia after a certain temporal delay during defined phases of the time course of the effects of large L-dopa doses. The D1 receptor agonist (+)-SKF 38393 potentiates both the hyperalgesic and antinociceptive effects of 100 mg/kg of L-dopa. It is suggested that L-dopa's net effect on pain is modulated from concentration-dependent, opposing effector systems involving both DA stimulatory and inhibitory receptor mechanisms. At high dosing, activation of D2 receptors enhancing DA functional activity produces an antinociceptive response that normally outweighs the hyperalgesia, but this effect becomes dissociable with inhibition of central DA activity.

Separate noradrenergic receptors could mediate clonidine-induced antinociception.

The antinociceptive effect of clonidine on a response to painful stimulation mediated by supraspinal structures was recorded after s.c. administration of the drug in doses from 50 up to 2000 micrograms/kg. Both low and high doses of clonidine produced antinociception on the pain threshold studied. A careful analysis of the dose-response curve showed, however, that the net effect recorded involved the sum of responses from at least two functional systems or receptor sites. When the dose-response relationship of clonidine-induced antinociception was studied after alpha-1 receptor blockade by means of phenoxybenzamine, it was found that this effect comprised contributions from different neurotransmitter systems. These results are discussed in terms of the possibility that separate adrenergic receptors mediate clonidine antinociception at different levels in the pain transmission. The determinant of the population of receptors being activated after systemic administration of clonidine is the dose given.

Comparison of pharmacodynamic effects and plasma levels of oral and rectal ergotamine.

Plasma levels and the vasoconstrictive effect of 1 mg ergotamine tartrate given as tablets or suppositories were compared. In a crossover study, eight male volunteers received tablets or suppositories containing ergotamine in a drug combination (Anervan) and, as a control, suppositories without ergotamine. Blood sampling and measurement of toe-arm systolic gradients with a strain-gauge technique were done for up to 6 h and again after 24 h and 48 h. Only 29 of 160 blood samples contained detectable (greater than 0.1 ng/ml) amounts of ergotamine, and kinetic comparison could not be performed. Only ergotamine-containing suppositories caused a significant (p less than 0.008) decrease in toe-arm systolic gradient which was significantly different (p less than 0.003) from the effects of ergotamine tablets and control suppositories. Rectal ergotamine is thus more biologically active, for the factor used, than oral ergotamine. We suggest that a rectal dose of 1 mg ergotamine tartrate should be tried as the initial dose in the treatment of migraine attacks.

Pharmacokinetic studies of theophylline in horses.

The pharmacokinetics of theophylline were determined in Standardbred trotters after single intravenous and oral administration. A bi-exponential equation was fitted to the intravenous data and a tri-exponential equation to the oral data. The biological half-life of theophylline was found to be 14.8 h, the volume of distribution 1.02 l/kg and the total plasma clearance 0.86 ml/kg/min. The oral absorption of the drug was complete (bioavailability 108%) and rapid (absorption half-life 0.4 h).

Clonidine twice daily in hypertension. Effects of two dosage regimens on blood pressure, side-effects and plasma clonidine concentrations.

The effects of two b.i.d. dosing schedules of clonidine on blood pressure, side-effects and plasma concentration of clonidine were studied in a randomized cross-over study. The blood pressures of 10 hypertensive inpatients on diuretic treatment were recorded every 3-4 hours throughout the study. A twice-daily regimen with 0.075 mg clonidine administered at 8 a.m. and 0.15 mg at 10 p.m. resulted in a wider fluctuation of blood pressure than the same doses given at 8 a.m. and 4 p.m. The most conspicuous finding was the significant rise (p less than 0.001) of diastolic blood pressure at 8 p.m., when clonidine was given at 8 a.m. and 10 p.m. The overall mean values of supine systolic and diastolic blood pressures were normotensive and did not differ from each other in the two dosing schedules. There were no obvious differences in subjective side-effects between the two regimens. Predose clonidine concentrations varied interindividually between 0.15 and 1.12 ng/ml, but the fluctuation in one and the same subject was small and related to dose and its timing. Thus, twice-daily dosing of clonidine seems to result in a satisfactory blood pressure reduction. Fluctuation of blood pressure is greater when the evening dose is given at 10 p.m.

Optimal routes of administration of ergotamine tartrate in cluster headache patients. A pharmacokinetic study.

Bioavailability and rate of absorption of ergotamine were studied in eight cluster headache patients outside attacks. In a cross-over design, approximately 2 mg ergotamine tartrate was administered as effervescent tablets, suppositories, and from an inhalation device, with 0.25 mg intravenously as the reference. Ergotamine in plasma was measured by high performance liquid chromatography with fluorescence detection from 5 to 420 min. For all three routes of administration, a similar low (0.5-4.2%) bioavailability of ergotamine was estimated. Only inhalation of ergotamine resulted in early (at 5 min) peak concentrations of ergotamine in plasma and is therefore most likely to relieve the short-lived attacks of cluster headache. The inhalation route for ergotamine poses problems, however, and we suggest ways of improving the inhalation device.