Involvement of Cholinergic and Opioid Receptor Mechanisms in Nicotine-Induced Antinociception

Abstract: In this work we have studied the influences of nicotinic agents on the antinociception of morphine in formalin test. Nicotine (0.001-0.1 mg/kg) induced antinociception in mice in a dose-dependent manner in the early phase of formalin test, and also potentiated the morphine effect. The nicotinic receptor antagonist, mecamylamine (0.5 mg/kg), but not hexamethonium decreased the antinociception induced by nicotine (0.1 mg/kg) in both phases. The muscarinic receptor antagonist atropine (5 and 10 mg/kg) also decreased the response of nicotine. Mecamylamine, hexamethonium or atropine did not alter morphine antinociceptive response, while naloxone decreased responses induced by nicotine or morphine. The antagonists by themselves did not elicit any response in formalin test, however, high doses of mecamylamine tend to increase pain response. It is concluded that central cholinergic and opioid receptor mechanisms may be involved in nicotine-induced antinociception.     

Adenosine receptor agonists or antagonists alter antinociception, but did not show an interaction with imipramine-induced antinociception in the formalin test in mice.

In this study, the antinociceptive effect of imipramine and adenosine agents, and interactions between imipramine with adenosine drugs in mice in the formalin test, have been investigated. Intraperitoneal administration of different doses of imipramine (10, 20, 30 and 40 mg/kg) induced a dose dependent antinociception in mice, in both the first and second phases of the formalin test. The adenosine A(1) receptor agonists, R-(N(6)-phenylisopropyl)-adenosine (0.015, 0.03 and 0.1 mg/kg) and 5'-N-ethylcarboxamide adenosine (0.001, 0.005, 0.01 mg/kg), but not 2-chloroadenosine (0.1 and 0.5 mg/kg), and the adenosine receptor antagonist, 8-phenyltheophylline (0.1, 0.5 and 1 mg/kg), but not 1,3-dipropyl-7-methyl-xanthine (0.5 and 5 mg/kg), also produced an antinociceptive response. Lower dose of the adenosine receptor antagonist theophylline induced antinociception, while a higher dose of the drug caused hyperalgesia. Theophylline reduced the response induced by imipramine. It is concluded that adenosine systems are not involved in imipramine responses in the formalin test.     

Imipramine-induced antinociception in the formalin test. Receptor mechanisms involved and effect of swim stress

This study concerned the effect of swim stress on imipramine-induced antinociception in mice. The data showed that intraperitoneal (i.p.) administration of different doses of imipramine (10-40 mg/kg) and 0.5-3 min of swim stress (17 degrees C) induced antinociception in the first and second phases of the formalin test. Low period of swim stress (10 s) with low doses of imipramine (2.5, 5 and 10 mg/kg i.p.), which did not have any effect by themselves, in combination showed antinociception in the second phase of the test. Either yohimbine (0.5 mg/kg i.p.) or naloxone (1 mg/kg i.p.) reversed the response induced by the combination of low doses of imipramine plus swim stress. Yohimbine (1 mg/kg i.p.) decreased the response of imipramine (20 mg/kg i.p.) but not that of 30 s swim stress in the second phase. However, naloxone (1 mg/kg i.p.) reduced the antinociception induced by imipramine (20 mg/kg i.p.) or 30 s swim stress in the second phase of the test, the combination of imipramine with swim stress was not altered by yohimbine or naloxone. Prazosin induced antinociception by itself in the first phase of the test and increased swim-stress-induced antinociception with no interaction. It is concluded that antinociception induced by imipramine in the second phase of formalin test may be mediated through alpha(2)-adrenoceptor antagonists. The results indicate that the responses of swim stress and imipramine may be mediated by an opioid mechanism, but the combination of both drugs induced higher antinociceptive effects.     

Effect of alpha-adrenoceptor agonists and antagonists on imipramine-induced antinociception in the rat formalin test

In this study, the effect of central administration of the alpha-adrenoceptor agents on the antinociception induced by imipramine in the formalin test has been investigated. Intraperitoneal (IP) administration of different doses of imipramine (10-80 mg/kg) and intracerebroventricular (ICV) administration of the alpha(2)-adrenoceptor agonist clonidine (0.05-0.8 microg/rat) elicited a dose-dependent antinociception in the both phases of the test. Furthermore, different doses of clonidine (0.05-0.2 microg/rat) increased the antinociception induced by imipramine (10 and 20 mg/kg). The alpha(2)-adrenoceptor antagonist yohimbine (2 microg/rat, ICV) reduced the response of a low dose imipramine (10 mg/kg, IP) plus different doses of clonidine (0.05, 0.1 and 0.2 microg/rat, ICV), but did not alter the response induced by higher doses of imipramine (20 and 40 mg/kg) alone or in combination with clonidine. Yohimbine by itself elicited no effect. The alpha(1)-adrenoceptor agonist phenylephrine (0.07-1.5 microg/rat) induced antinociception in both phases of the formalin test, but did not alter the imipramine-induced antinociception. The alpha(1)-adrenoceptor antagonist prazosin neither elicited antinociception nor altered the imipramine response. Yohimbine (2 microg/ rat, ICV) in combination with prazosin (0.5 microg/rat, ICV) caused more inhibition of the response of imipramine or imipramine plus clonidine. Therefore, it is concluded that alpha(2)-adrenoceptor mechanism may be involved in the imipramine-induced antinociception.     

Effect of imipramine on tolerance to morphine antinociception in the formalin test

In this study, the effect of imipramine on morphine antinociception in tolerant and non-tolerant mice in the formalin test, was investigated. Subcutaneous administration of different test doses of morphine (3, 6 and 9 mg/kg) and intraperitoneal injection of test doses of imipramine (10, 20 and 40 mg/kg) induced a dose-dependent antinociception in non-tolerant mice, both in the first and second phases of the formalin test. The combination of morphine (1 mg/kg) with imipramine (10 mg/kg) showed a potentiated response in the second phase of the test. Combination of a single dose of morphine (1.5 mg/kg) with lower doses of imipramine (2, 4 and 8 mg/kg) did not show potentiation. The antinociceptive response of either morphine or morphine plus imipramine was reduced by the opioid receptor antagonist naloxone (2 mg/ kg). In order to induce tolerance, mice were treated subcutaneously with morphine (50 mg/kg) once daily for 3 days. On day 4, the antinociceptive effect of test doses of morphine or imipramine were assessed. Tolerance to the responses of test doses of morphine (3, 6 and 9 mg/kg), but not imipramine (10, 20 and 40 mg/kg) in both phases of the test was observed. Administration of lower dose of imipramine (4 mg/kg) before the test doses of morphine (3, 6 and 9 mg/kg) was not able to alter the expression of morphine tolerance. When imipramine was used during development of tolerance, either on days 1 and 2 or on days 2 and 3, the morphine tolerance in the second phase of the test was reduced. It is concluded that opioid receptor mechanism(s) may mediate the antidepressant-induced antinociception, however, imipramine may be useful in inhibiting morphine tolerance.     

GABA(B) receptor mechanism and imipramine-induced antinociception in ligated and non-ligated mice

This study concerned the effects of GABA(B) receptor agents on imipramine-induced antinociception in ligated and non-ligated mice in hot-plate test. The data showed that different doses of morphine (3, 6 and 9 mg/kg) induced a dose-dependent antinociception in non-ligated or ligated mice. However, the opioid response was decreased in the ligated animals. Intracerebroventricular (i.c.v.) administration of imipramine (5, 10, 20 and 40 microg/mouse) did not induce antinociception in either non-ligated or ligated mice. However, the response induced in the ligated mice was less than that induced in the non-ligated animals. Intraperitoneal (i.p.) administration of imipramine (10, 20, 30 and 40 mg/kg) induced antinociception in both ligated and non-ligated animals. The responses to the drug were not significantly different in the two groups. Administration of baclofen either i.c.v. (0.125, 0.25 and 0. 5 microg/mouse) or i.p. (0.5, 1, 2 and 4 mg/kg) induced antinociception. The response to the drug was not significantly different in ligated and non-ligated mice. I.c.v. administration of a lower dose of baclofen (0.125 microg/mouse) with different doses of imipramine (2.5, 5 and 10 mg/kg) potentiates the response of imipramine. This effect was reduced by i.c.v. injection of GABA(B) receptor antagonist, CGP35348 [P-(3-aminopropyl)-p-diethoxymethyl-phosphinic acid] (20 microg/mouse). The higher dose of antagonist (20 microg/mouse) also decreased the response induced by baclofen or imipramine. CGP35348 itself (2.5, 5, 10 and 20 microg/mouse) induced dose-dependent antinociception with no significant difference in the ligated and non-ligated mice. It is concluded that a GABA receptor mechanism(s) may modulate the antidepressant-induced antinociception.     

Cross-tolerance between antinociception induced by swim-stress and morphine in formalin test

The present study investigated cross-tolerance between antinociception induced by water swim-stress and morphine in the formalin test. Intraperitoneal administration of morphine (3, 6 and 9 mg/kg) induced dose-dependent antinociception in both phases of the formalin test. Mice treated with a lower dose of morphine (25 mg/kg), once daily for 3 days, showed tolerance to antinociception induced by a lower test dose of morphine (3 mg/kg). Similar repeated treatments with a higher dose of morphine (50 mg/kg) produced tolerance to antinociception induced by different test doses of morphine (3, 6 and 9 mg/kg). Exposure to water swim-stress, once daily for 2 or 3 days in order to induce tolerance, also decreased morphine-induced antinociception. Swim-stress exposure for 2 or 3 days also tends to potentiate tolerance induced by a lower dose of morphine. Acute swim-stress of different durations (0.5, 1 and 3 min) induced antinociception in both phases of the formalin test, which was not reduced by naloxone, but showed even more antinociception in the second phase. The response to swim stress was decreased in mice treated with higher doses of morphine, but not those animals that received swimming stress (3 min) once daily for 2-3 days, in order to induce habituation to swim-stress-induced antinociception. The results may indicate a possible cross-tolerance between antinociception induced by morphine and by swim stress.     

Effect of intracerebroventricular injection of GABA receptor agents on morphine-induced antinociception in the formalin test

In the present study, the effects of gamma-aminobutyric acid (GABA) receptor agonists and antagonists on antinociception induced by morphine in the formalin test were investigated in rats. Intraperitoneal (i.p.) injection of different doses of morphine (1, 3, 6 and 9 mg/kg) and intracerebroventricular (i.c.v.) injection of different doses of muscimol (0.5, 1 and 2 microg per rat) or baclofen (0.25, 0.5 and 1 microg per rat) induced a dose-related antinociception in the both first and second phases of the formalin test. The responses induced by muscimol or baclofen in both phases were reduced by bicuculline or CGP35348 [p-(3-aminopropyl)-p-diethoxymethyl-phosphinic acid], respectively. Bicuculline alone has produced antinociception in the second phase and CGP35348 alone has had antinociception in both phases of the formalin test. Morphine in combination with different doses of muscimol or baclofen did not elicit potentiation. The opioid receptor antagonist naloxone reduced the response induced by muscimol in the second phase and baclofen in both phases of the formalin test. It may be concluded that central GABA(A) and GABA(B) receptor stimulation induces antinociception in the formalin test. However, the antinociception induced by GABA receptor agonists may be mediated partly through supraspinal opioid receptor mechanisms and, for the GABA(B) receptor agonist, through spinal and supraspinal opioid receptor mechanisms.     

Adenosine receptor mediates nicotine-induced antinociception in formalin test.

In this study, the effect of adenosine receptor agents on nicotine induced antinociception, in formalin test, has been investigated. Intraperitoneal (i.p.) administration of different doses of nicotine (0.1, 1, 10 and 100 microgkg(-1)) induced a dose-dependent antinociception in mice, in the both first and second phases of the test. Adenosine receptor antagonist, theophylline (5, 10, 20 and 80 mgkg(-1), i.p.) also induced antinociception in the both phases, while a dose of the drug (40 mgkg(-1), i.p.) did not induce any response. Theophylline reduced antinociception induced by nicotine in both phases of formalin test. The A(2) receptor agonist, 5'-N-ethylcarboxamide adenosine (NECA; 1 and 5 microgkg(-1), i.p.) also produced antinociception, which was reversed with different doses of theophylline (5, 10, 20 and 40 mgkg(-1), i.p.). But administration of the adenosine receptor agonist, NECA did not potentiate the response of nicotine. It is concluded that adenosine system may be involved in modulation of antinociception induced by nicotine.     

Effect of alpha-adrenoceptor agents on imipramine-induced antinociception in nerve-ligated mice.

In this study, the effects of adrenoceptor agonists and antagonists on antinociception induced by imipramine in sciatic-nerve-ligated mice were investigated. The response of different doses of morphine, imipramine and adrenoceptor agonists and antagonists was examined 14 days after unilateral nerve-ligation in the hot-plate test. Intraperitoneal injection of different doses of morphine (3, 6 and 9 mg/kg), imipramine (10, 20 and 40 mg/kg), the alpha(2)-adrenoceptor agonist, clonidine (0.05, 0.1 and 0.2 mg/kg) or the alpha(1)-adrenoceptor agonist, phenylephrine (2, 4 and 8 mg/kg) induced dose-related antinociception in both intact and nerve-ligated mice. The antinociception induced by morphine but not that of imipramine, clonidine or phenylephrine, in nerve-ligated mice was significantly less than that induced in intact animals. Imipramine in combination with clonidine tends to induce a higher response, but the combination of imipramine with phenylephrine did not lead to significant potentiation. The alpha(2)-adrenoceptor antagonist, yohimbine, reduced the response induced by imipramine or imipramine plus clonidine in intact and nerve-ligated animals. However, the alpha(1)-adrenoceptor antagonist, prazosin, did not alter imipramine response. It may be concluded that imipramine induced antinociception in both intact and nerve-ligated mice through an alpha(2)-adrenoceptor mechanism(s).     

Baclofen and antidepressant – induced antinociception in formalin test: possible GABAB mechanism involvement

In this study, the influences of GABA_B agents on antidepressant-induced antinociception in the mouse formalin test have been investigated. The GABA_B receptor agonist baclofen (2.5, 5 and 10 mg/kg) induced a dose-dependent antinociception in the second phase of the formalin test. This response was inhibited by the GABA_B receptor antagonist, CGP35348 [P-(3-aminopropyl)-p-diethoxymethyl-phosphinic acid], in a dose-dependent manner. The antagonist by itself also induced antinociception. Single administration of the antidepressants citalopram (10, 20, 40 and 80 mg/kg), desipramine (20, 40, 80 mg/kg) or imipramine (10, 20 and 40 mg/kg) also induced antinociception in both phases of the formalin test. CGP35348 (100 and 200 mg/kg) pretreatment reduced the response induced by the tricyclic antidepressants. A combination of baclofen with the tricyclic antidepressant did not potentiate antinociception induced by antidepressants, but a decrease in the response induced by higher dose of baclofen was shown. It is concluded that GABA mechanism(s) may modulate the antidepressant-induced antinociception. Received: 3 August 1998/Final version: 28 September 1998     

Baclofen-induced antinociception and nicotinic receptor mechanism(s)

In this study, the influences of nicotinic receptor agents on baclofen-induced antinociception in the tail-flick test have been studied. Intraperitoneal administration of baclofen (2.5, 5 and 10 mg/kg) to mice induced a dose-dependent antinociception in the tail-flick test. Subcutaneous injection of nicotine (0.5-2.5 mg/kg) also caused a dose-dependent antinociceptive response. Intracerebral (10 and 20 microg/mouse) but not intraperitoneal administration of hexamethonium (5 and 10 mg/kg) to mice decreased the response of both nicotine and baclofen. However, administration of the GABA(B) antagonist CGP 35348 (100 and 200 mg/kg) decreased the response induced by baclofen but not by nicotine. It is concluded that at least part of the baclofen-induced antinociception may be mediated through a nicotinic mechanism.     

Baclofen-Induced Antinociception and Nicotinic Receptor Mechanism(s)

Abstract In this study, the influences of nicotinic receptor agents on baclofen-induced antinociception in the tail-flick test have been studied. Intraperitoneal administration of baclofen (2.5, 5 and 10 mg/kg) to mice induced a dose-dependent antinociception in the tail-flick test. Subcutaneous injection of nicotine (0.5–2.5 mg/kg) also caused a dose-dependent antinociceptive response. Intracerebral (10 and 20 μg/mouse) but not intraperitoneal administration of hexamethonium (5 and 10 mg/kg) to mice decreased the response of both nicotine and baclofen. However, administration of the GABA_B antagonist CGP 35348 (100 and 200 mg/kg) decreased the response induced by baclofen but not by nicotine. It is concluded that at least part of the baclofen-induced antinociception may be mediated through a nicotinic mechanism.     

Dopamine receptor mechanism(s) and antinociception and tolerance induced by swim stress in formalin test

In the present study, involvement of D1 and D2 dopamine receptors in the antinociception and tolerance induced by water swim stress in the formalin test has been investigated. Water swim stress at 20 degrees C temperature induced antinociception in both phases of the formalin test. Intraperitoneal administration of the D2 dopamine receptor antagonist, sulpiride (25 and 50 mg/kg) reduced swim stress-induced antinociception in the second phase of the formalin test. A higher dose of the D1 dopamine receptor antagonist, SCH23390 (0.1 mg/kg, intraperitoneal) also reduced swim stress-induced antinociception in both phases of the test. Exposure to 3 min water swimming stress, once daily for 3 days, induced tolerance to swim stress-induced antinociception in the second phase of the formalin test. Administration of sulpiride (12.5, 25 and 50 mg/kg), during exposure to water swimming stress (once daily for 3 days), decreased tolerance in the second phase, whereas the antagonist (12.5 and 50 mg/kg) increased pain scores in the first phase of the formalin test. Sulpiride (25 mg/kg) treatment however, once daily for 3 days with no water swimming stress, did not alter swim stress-induced antinociception (0.5, 1 and 3 min tests). Similarly, repeated treatment with SCH23390 (0.05 mg/kg) and water swimming stress did not alter tolerance induced by water swimming stress. Repeated administration of the antagonist in the absence of water swimming stress also did not change swim stress-induced antinociception. The results may indicate a possible involvement of both dopamine D1 and D2 receptors in the antinociception induced by swim stress and D2 receptor mechanism in the tolerance induced by repeated swim stress.     

The effects of nitric oxide on the acquisition and expression of nicotine-induced conditioned place preference in mice

In the present study, the possible role of nitric oxide on the conditioned place preference (CPP) induced by nicotine in mice was investigated. Intraperitoneal (i.p.) injections of nicotine (1 mg/kg) and the nitric oxide (NO) precursor, L-arginine (200 and 500 mg/kg), produced significant place preference. However, injection of mecamylamine (0.05 and 0.1 mg/kg; i.p.) or the NO synthase (NOS) inhibitor, L-Nitro-amino-methyl-ester, L-NAME (5-20 mg/kg; i.p.), had no effect. Ineffective doses of nicotine in combination with ineffective doses of L-arginine produced significant place preference. Administration of L-arginine (50, 100 and 150 mg/kg; i.p.) on the test day reduced the expression of nicotine-induced place preference. Nicotine injection (0.25, 0.5 and 0.75 mg/kg) on the test day reduced the expression of place preference induced by L-arginine, while both mecamylamine (0.05 and 0.1 mg/kg) and L-NAME (5, 10 and 20 mg/kg) inhibited the acquisition of place preference induced by nicotine (1 mg/kg) and L-arginine (200 mg/kg). Moreover, neither of the antagonists reduced the expression of nicotine- or L-arginine-induced place preference. It is suggested that nitric oxide may play an important role in nicotine-induced place preference.     

Nicotine potentiates sulpiride-induced catalepsy in mice

The effects of nicotine on sulpiride-induced catalepsy in mice were investigated. Sulpiride (12.5-100 mg/kg) induced a low degree of catalepsy in mice which was dose dependent. Nicotine (0.0001-1 mg/kg) caused an even lower degree of catalepsy. When the drugs were co-administered a much higher cataleptogenic response was obtained. The potentiation of the effect of sulpiride by nicotine was elicited by 0.5 mg/kg or higher doses of the drug. The central nicotinic receptor antagonist mecamylamine (1-3 mg/kg) and the peripheral antagonist hexamethonium (5 and 10 mg/kg) decreased the response induced by the combination of nicotine and sulpiride. Higher doses of the cholinoceptor antagonist atropine (10 mg/kg) also reduced the catalepsy induced by the drug combination. It is concluded that nicotine potentiates sulpiride-induced catalepsy through activation of cholinergic mechanism(s) and that the central nicotinic mechanism mediates nicotine's action.     

Effect of nicotine on apomorphine-induced licking behaviour in rats.

In the present study, the dopaminergic receptor agonist apomorphine (0.1, 0.25 and 0.5 mg/kg) induced a dose-dependent licking in rats. Nicotine administration (0.025-250 microg/kg) altered the apomorphine-induced licking. The lower doses of nicotine (0.05 and 0.5 microg/kg) increased while the higher dose of the drug (250 microg/kg) reduced the apomorphine response. The antimuscarinic drug atropine (2.5 and 5 mg/kg) reduced the effects of apomorphine or nicotine plus apomorphine. The central nicotinic receptor antagonist mecamylamine (0.05, 0.25 and 0.5 mg/kg) also reduced the response induced by apomorphine or nicotine plus apomorphine. However, the peripheral nicotinic receptor antagonist hexamethonium (2.5, 5 and 10 mg/kg) reduced the response induced by nicotine plus apomorphine but not that elicited by apomorphine alone. The results indicate that the nicotinic receptor mechanism(s) may interact with apomorphine-induced licking in rats. Although central nicotinic and cholinergic mechanisms may be involved in the licking induced by apomorphine, peripheral nicotinic mechanism may be involved in the nicotine-induced increased apomorphine effect.     

Effects of drugs on behaviour of aggressive mice

1 The occurrence of 11 aggressive and non-aggressive activities was observed in aggressive male mice treated with drugs in paired interactions with non-aggressive males given water. Effects of chlordiazepoxide, diazepam, barbitone, chlorpromazine, imipramine, (+)-amphetamine, lysergic acid diethylamide (LSD) all given orally and of intraperitoneal scopolamine were investigated.2 Scopolamine (0.25 and 0.75 mg/kg), (+)-amphetamine (0.25 and 1 mg/kg), chlorpromazine (2.5 mg/kg), diazepam (10 mg/kg) and chlordiazepoxide (50 mg/kg) reduced aggressive activities (attacks, aggressive unrest) without inhibiting walking across the cage or rearing in the aggressive mice. Thus, the inhibition of aggression induced by these drugs does not seem to be due to neuromuscular impairment and seems to this extent specific. On the other hand, imipramine lessened aggressive activities only at a dose (80 mg/kg) which also decreased walking across the cage and rearing. Barbitone or LSD did not change aggression at either dose tested (20 and 60 or 0.01 and 1 mg/kg, respectively). Aggressive activities were increased significantly only by chlordiazepoxide at a dose of 5 mg/kg.3 (+)-Amphetamine (0.25 mg/kg) and scopolamine (0.75 mg/kg) increased escapes and alert postures, respectively, in the aggressive mice.4 Diazepam and chlordiazepoxide decreased tail rattling at 1 and 5 mg/kg, respectively, doses 10 times lower than those inhibiting attacks. The other drugs tested inhibited tail rattling only at doses reducing attacks. Tail rattling appears to be a convenient measure for testing effects of drugs on behavioural conflict.5 Diazepam (5 and 10 mg/kg), chlordiazepoxide (20 and 50 mg/kg), barbitone (60 mg/kg) and scopolamine (0.25 and 0.75 mg/kg) increased sociable activities (sniffing, following partners and climbing over them) whereas (+)-amphetamine, chlorpromazine, imipramine and LSD did not. Effects of the drugs on sociable activities in aggressive mice seem to correlate with their action on punished responding and other types of suppressed behaviour.     

Nicotine-induced grooming: a possible dopaminergic and/or cholinergic mechanism

The ability of nicotine, to induce grooming in rats was studied. Grooming was induced by i.p. injection of different doses (0.0675-0.5 mg/kg) of nicotine to rats. The effect was dose-dependent. However, the response was decreased with increasing doses of the drug from 0.25-0.5 mg/kg. Administration of the dopamine (DA) D1/D2 receptor agonist apomorphine (0.025-5 mg/kg, i.p.) also caused grooming in a dose-dependent manner. High doses of apomorphine (0.1-0.5 mg/kg, i.p.) also induced a lower degree of response. Combination of a low dose of nicotine (0.0675 mg/kg) with different doses of apomorphine did not show any interaction. However, there was an interaction between a high dose of nicotine and apomorphine. Thus, combination of a higher dose of nicotine (0.125 mg/kg) with apomorphine, reduced apomorphine-induced grooming. The muscarinic receptor antagonist atropine (5 and 10 mg/kg), peripheral nicotinic receptor antagonist hexamethonium (5 and 10 mg/kg), central nicotinic receptor antagonist mecamylamine (1 and 3 mg/kg) and D1 DA receptor antagonist SCH23390 (0.05 and 0.1 mg/kg) all decreased the response to nicotine. Atropine, mecamylamine and SCH23390 by themselves reduced spontaneous grooming. It is concluded that nicotine elicits grooming indirectly through a possible D1 dopaminergic mechanism. However, muscarinic and nicotinic cholinergic mechanism(s) may be involved.     

3-Methyl-5-hydroxy-5-trichloromethyl-1H-1-pyrazolcarboxyamide induces antinociception

The antinociceptive action of a novel pyrazole-derived compound, 3-methyl-5-hydroxy-5-trichloromethyl-1H-1-pyrazolcarboxyamide (MPCA) was evaluated using the formalin and tail-immersion tests in mice. Anti-inflammatory activity was assessed by paw plethysmometry in adult rats using the carrageenin-induced paw edema test. Subcutaneous administration of MPCA (22, 66, and 200 mg/kg) induced a dose-dependent decrease in the time spent licking during the neurogenic and inflammatory phases of the formalin test, and preadministration of naloxone (1 mg/kg, sc) did not prevent MPCA-induced (200 mg/kg, sc) antinociception. Naloxone decreased the spontaneous locomotor activity of mice, while MPCA had no effect on locomotion. In contrast, administration of the opioid antagonist caused a significant increase in the locomotor behavior of mice previously injected with MPCA. MPCA was devoid of antinociceptive action by the tail-immersion test and of anti-inflammatory activity. Moreover, MPCA had no effect on the motor performance of mice in the rotarod test. These results suggest that MPCA induces antinociception in the neurogenic and inflammatory phases of the formalin test, an effect that does not involve opioid receptors.