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.

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.

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.

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.

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.

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.

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.