Effects of scopolamine,physostigmine and chlordiazepoxide on punished and extinguished water consumption in rats

It has been postulated that behavioral inhibition due to punishment or extinction may be mediated by brain acetylcholine, and drugs which have disinhibitory action are thought to interact with this system. This notion was tested by comparing the effects of scopolamine, physostigmine and chlordiazepoxide on punished and extinguished water consumption. Scopolamine hydrobromide (0.3, 0.5 mg/kg, i.p.), a centrally and peripherally acting antimuscarinic agent and physostigmine sulfate, (0.3 mg/kg, i.p.), a centrally and peripherally acting acetylcholinesterase inhibitor, lowered both non-punished and punishment suppressed water intake and lick rate, whereas their quaternary analogs which primarily act in the periphery, had no significant effect at comparable dose levels. Scopolamine and physostigmine suppressed punished water consumption at lower dose levels than nonpunished intake. In contrast, chlordiazepoxide (5.0, 10.0, 20.0 mg/kg, i.p.) enhanced punished as well as non-punished water intake. In a further experiment comparing punishment and extinction suppression, scopolamine and physostigmine did not affect punished or extinguished water intake; chlordiazepoxide (5.0, 10.0, 20.0 mg/kg) reliably increased punished, but not extinguished licking on the water nozzle. These results suggest (1) that scopolamine and chlordiazepoxide do not act via a common mechanism, and (2) that punishment and extinction suppression are not a pharmacological entity.     

Pharmacological characterization of AM1710, a putative cannabinoid CB2 agonist from the cannabilactone class: antinociception without central nervous system side-effects

Cannabinoid CB₂ agonists produce antinociception without central nervous system (CNS) side-effects. This study was designed to characterize the pharmacological and antinociceptive profile of AM1710, a CB₂ agonist from the cannabilactone class of cannabinoids. AM1710 did not exhibit off-target activity at 63 sites evaluated. AM1710 also exhibited limited blood brain barrier penetration. AM1710 was evaluated in tests of antinociception and CNS activity. CNS side-effects were evaluated in a modified tetrad (tail flick, rectal temperature, locomotor activity and rota-rod). Pharmacological specificity was established using CB₁ (SR141716) and CB₂ (SR144528) antagonists. AM1710 (0.1-10 mg/kg i.p.) produced antinociception to thermal but not mechanical stimulation of the hindpaw. AM1710 (5 mg/kg i.p.) produced a longer duration of antinociceptive action than the aminoalkylindole CB₂ agonist (R,S)-AM1241 (1 mg/kg i.p.) at maximally antinociceptive doses. Antinociception produced by the low (0.1 mg/kg i.p.) dose of AM1710 was blocked selectively by the CB₂ antagonist SR144528 (6 mg/kg i.p.), whereas antinociception produced by the high dose of AM1710 (5 mg/kg i.p.) was blocked by either SR144528 (6 mg/kg i.p.) or SR141716 (6 mg/kg i.p.). AM1710 did not produce hypoactivity, hypothermia, tail flick antinociception, or motor ataxia when evaluated in the tetrad at any dose. In conclusion, AM1710, a CB₂-preferring cannabilactone, produced antinociception in the absence of CNS side-effects. Thus, any CB₁-mediated antinociceptive effects of this compound may be attributable to peripheral CB₁ activity. The observed pattern of pharmacological specificity produced by AM1710 is consistent with limited blood brain barrier penetration of this compound and absence of CNS side-effects.     

An antinociceptive profile of kojic amine: an analogue of gamma-aminobutyric acid (GABA)

Kojic amine [2-(aminomethyl)-5-hydroxy-4H-pyran-4-one], an analogue of gamma-aminobutyric acid (GABA), produced dose-related, but short-lived, antinociceptive activity in the 48 degrees C [ED50 = 9.2 (8.2-10.3) mg/kg i.p.] and 55 degrees C [ED50 = 13.8 (12.2-15.7) mg/kg i.p.] hot-plate tests in the mouse. The antinociceptive activity of kojic amine at 48 degrees C was found to be insensitive to bicuculline (1.0 mg/kg i.p.) and picrotoxin (0.5 mg/kg i.p.). At this temperature, antinociception was distinctly separate from the impairment of motor function (measured by a rotorod assay) and was not significantly affected by prior treatment with the cholinergic antagonist, atropine sulfate (10.0 mg/kg i.p.). However, at 55 degrees C, the antinociceptive effect of a large dose (20 mg/kg i.p.) of kojic amine was significantly attenuated by similar pretreatment with atropine sulfate, but not by the peripheral cholinergic antagonist, atropine methylnitrate (10.0 mg/kg i.p.). Kojic amine exhibited no significant interaction with haloperidol (0.5 mg/kg i.p.) at this temperature. In animals made tolerant to morphine, THIP or baclofen, there was analgesic cross-tolerance between kojic amine, morphine and baclofen but not between kojic amine and THIP. It is suggested that kojic amine-induced antinociception is similar to that produced by both THIP and baclofen. Thus, kojic amine represents a unique tool with which to study GABA-ergic antinociceptive processes.     

GABAergic and cholinergic mediation in the antinociceptive action of homotaurine.

1. The role of GABAergic and cholinergic mechanisms in the antinociceptive effect of homotaurine (22.25-111.24 mg/kg i.p.) in chemical (acetic acid) and thermal (tail flick, tail immersion) tests has been studied by means of the interaction with baclofen and anticholinergic drugs. 2. Baclofen (2 mg/kg p.o.) and scopolamine sulfate (2.5 mg/kg i.p.) potentiate the antinociceptive effect of the amino acid in the chemical test. 3. Bicuculline (1 mg/kg i.p.) pretreatment does not modify the antinociceptive effect of homotaurine in the tail immersion and tail flick tests. 4. Scopolamine sulfate and methylnitrate (1 mg/kg i.p.) antagonise the effect of homotaurine (111.24 mg/kg i.p.) in the tail flick test. 5. The above results imply that peripheral GABAB and central cholinergic mechanisms play a role in the antinociceptive effect of homotaurine.     

Dopaminergic involvement in adenosine A1 receptor-mediated antinociception in the tail flick latency model in mice

The interaction between the adenosinergic and dopaminergic systems in nociception was assessed in the tail flick latency (TFL) test in mice. Adenosine exhibited qualitatively different responses depending on the dose: Adenosine 10 and 100 mg/kg i.p. caused antinociception as evidenced by an increase in TFL while the middle dose of 30 mg/kg decreased TFL. On the other hand, the specific adenosine A1 receptor agonist N6-cyclopentyladenosine (CPA) at doses of 0.05, 0.1, 0.25 and 0.5 mg/kg (i.p.) resulted in dose-dependent antinociception. The antinociceptive effect of CPA was reversed by classical albeit nonspecific adenosine receptor antagonist theophylline (5 mg/kg) at a dose which had no effect on TFL per se. A low dose (1 mg/kg i.p.) of the dopaminergic agonist apomorphine caused an early mild hyperalgesic response while the high dose (10 mg/kg i.p.) had no significant effect on TFL. The antinociceptive effect of CPA was attenuated by pretreatment with low dose apomorphine while pretreatment with the high dose caused mild but insignificant potentiation. Theophylline, when administered prior to apomorphine failed to modify the nociceptive response. The results suggest that an interaction between adenosine and dopamine may be involved in nociception.     

The involvement of central cholinergic system in (+)-matrine-induced antinociception in mice

The antinociceptive effect of (+)-matrine was examined in mice by writhing, tail-pressure and hot-plate tests. (+)-Matrine (5, 10 and 20 mg/kg s.c.) produced antinociception in a dose-dependent manner. In hot-plate test, the antinociception produced by (+)-matrine (10 mg/kg s.c.) was attenuated by muscarinic receptor antagonists atropine (5 mg/kg i.p.) and pirenzepine (0.1 mug/mouse i.c.v.) and acetylcholine depletor hemicholinium-3 (HC-3) (1 mug/mouse i.c.v.), but not by opioid receptor antagonist naloxone (2 mg/kg i.p.), dopamine D(2) receptor agonist (-)-quinpirole (0.1 mg/kg i.p.) or catecholamine depletor reserpine (2.5 mg/kg i.p.). Radioligand binding assay demonstrated that (+)-matrine had no affinity for mu-, kappa- or delta-opioid receptors in a wide concentration range (1 x 10(-11)-1 x 10(-3) M). The results suggest that (+)-matrine exerts its antinociceptive effect through multiple mechanism(s) such as increasing cholinergic activation in the CNS rather than acting on opioid receptors directly.     

L-NAME, a nitric oxide synthase inhibitor, modulates cholinergic antinociception.

Systemic administration of sumatriptan and buspirone (20 mg/kg: 5-HT1A agonists) produced antinociception against acetic acid-induced writhing. The antinociceptive effect was potentiated by cholinomimetic physostigmine (0.05 mg/kg i.p.) and blocked by the muscarinic antagonist atropine (5 mg/kg i.p.). Naloxone, an opiate antagonist, failed to reverse the sumatriptan- or buspirone-induced antinociception, but pindolol (10 mg/kg), a nonselective 5-HT1A antagonist, blocked this response. Sumatriptan- or buspirone-induced antinociception was significantly potentiated by L-NAME (a nitric oxide [NO] synthase inhibitor) although L-NAME (20 mg/kg) given alone had no effect on the nociceptive threshold. Recent studies have suggested that the L-arginine/NO/cGMP pathway is involved in the modulation of pain perception. The present results suggest that NO may play a role in cholinergic antinociception-mediated 5-HT1A receptor stimulation and that NO exerts an inhibitory action on cholinergic analgesia.     

Antinociceptive effect of L-arginine on the carrageenin-induced hyperalgesia of the rat: possible involvement of central opioidergic systems.

L-arginine is considered to be a precursor substance of kyotorphin (tyrosyl-arginine), a [Met5]enkephalin releaser with antinociceptive action. We examined the antinociceptive effect of L-arginine in rats. L-Arginine (300-1000 mg/kg) administered subcutaneously (s.c.) elicited antinociception (assessed by the Randall-Selitto method) in rats with a carrageenin-treated hindpaw. Naloxone (2 mg/kg s.c.) but not N-methyl-levallorphan (20 mg/kg s.c.), a peripherally selective opioid antagonist, inhibited L-arginine-induced antinociception. Intracerebroventricular administration of L-arginine (0.2-1.0 mg/rat) produced a dose-related inhibition of the carrageenin-induced hyperalgesia. Intraplantar (i.pl.) injection of L-arginine (0.5-1.0 mg/paw) also induced antinociception, which was resistant to naloxone (2 mg/kg s.c.) but was antagonized by methylene blue (0.5 mg/paw i.pl.), a guanylate cyclase inhibitor. L-Arginine (1000 mg/kg s.c.) did not inhibit edema formation in the carrageenin-treated rat hindpaw. These results suggest that systemically administered L-arginine produces mainly an antinociceptive effect mediated by central opioidergic mechanisms in rats with carrageenin-induced hyperalgesia.     

Behavioural analysis of changes in nociceptive thresholds produced by remoxipride in sheep and rats

The antinociceptive potential of remoxipride was investigated in sheep and rats with concurrent motor function assessments. Previous studies of sheep given intravenous remoxipride have revealed increases in mechanical nociceptive thresholds. Here, further investigation in sheep demonstrated elevated thermal nociceptive thresholds with no effect on subjectively assessed sedation or motor impairment scores. However, in rats, the dose of remoxipride (100 mg/kg i.p.) required to produce nociceptive thresholds similar to those elicited by morphine (30 mg/kg i.p.), itself reduced rotarod performance. Medetomidine (200 μg/kg i.p.) evoked sedation without influencing rotarod performance or antinociception. The antinociceptive, motor deficit and cataleptogenic actions of remoxipride were similar to those induced by two other dopamine antagonists, haloperidol (5 mg/kg) and raclopride (16 mg/kg i.p). Tocainide (100 mg/kg i.p.) induced thermal antinociception with normal rotarod performance and no catalepsy suggesting that Na⁺ channel blockade by remoxipride is not responsible for the changes in nociceptive thresholds. This study emphasizes the importance of motor function assessment during acute antinociceptive testing.     

The involvement of endogenous opioid mechanisms in the antinociceptive effects induced by antidepressant drugs, desipramine and trimipramine

The present study was designed to investigate the involvement of endogenous opioid systems in the antinociception induced by the antidepressant drugs, desipramine and trimipramine. For this purpose, the antinociceptive effects of desipramine (7.5 and 15.0 mg/kg i.p.) and trimipramine (5.0 and 10.0 mg/kg i.p.) were compared to that induced by morphine (0.2 and 2.0 mg/kg i.p.) in the tail-clip model in mice. Naloxone (0.3 and 3.0 mg/kg i.p.), a non-specific opioid receptor antagonist, inhibited morphine-induced antinociception in mice, whereas the antinociceptive effects of antidepressant drugs were found to be resistant to naloxone blockade to some extent, since only the higher concentration of naloxone (3.0 mg/kg i.p.) caused significant inhibition of the effects of antidepressant drugs. In contrast, naltrindole (1.0 mg/kg i.p.), a specific delta-receptor antagonist, inhibited antinociception induced by desipramine and trimipramine in this test, while it inhibited the antinociceptive effect of morphine only partly. None of the opioid antagonists produced a significant effect in the tail-clip experiment when they were injected alone. Based on these findings, we concluded that endogenous opioids are involved in the antinociceptive effects of the antidepressant drugs using different mechanisms.     

Do Diuretics have Antinociceptive Actions: Studies of Spironolactone,Eplerenone, Furosemide and Chlorothiazide,Individually and with Oxycodone and Morphine

Spironolactone, eplerenone, chlorothiazide and furosemide are diuretics that have been suggested to have antinociceptive properties, for example via mineralocorticoid receptor antagonism. In co‐administration, diuretics might enhance the antinociceptive effect of opioids via pharmacodynamic and pharmacokinetic mechanisms. Effects of spironolactone (100 mg/kg, i.p.), eplerenone (100 mg/kg, i.p.), chlorothiazide (50 mg/kg, i.p.) and furosemide (100 mg/kg, i.p.) were studied on acute oxycodone (0.75 mg/kg, s.c.)‐ and morphine (3 mg/kg, s.c.)‐induced antinociception using tail‐flick and hot plate tests in male Sprague Dawley rats. The diuretics were administered 30 min. before the opioids, and behavioural tests were performed 30 and 90 min. after the opioids. Concentrations of oxycodone, morphine and their major metabolites in plasma and brain were quantified by mass spectrometry. In the hot plate test at 30 and 90 min., spironolactone significantly enhanced the antinociceptive effect (% of maximum possible effect) of oxycodone from 10% to 78% and from 0% to 50%, respectively, and that of morphine from 12% to 73% and from 4% to 83%, respectively. The brain oxycodone and morphine concentrations were significantly increased at 30 min. (oxycodone, 46%) and at 90 min. (morphine, 190%). We did not detect any independent antinociceptive effects with the diuretics. Eplerenone and chlorothiazide did not enhance the antinociceptive effect of either opioid. The results suggest that spironolactone enhances the antinociceptive effect of both oxycodone and morphine by increasing their concentrations in the central nervous system.     

Mechanisms of L-NG-nitro arginine methyl ester-induced antinociception in mice: a role for serotonergic and adrenergic neurons.

1. The mechanisms involved in the antinociceptive action of L-NG-nitro arginine methyl ester (L-NAME) were investigated in mice. 2. Intraperitoneal administration of L-NAME produced a dose-dependent antinociception in the tail-flick, hot-plate and phenyl-p-quinone-induced writhing tests. 3. Pretreatment with the catecholamine depletors 6-hydroxydopamine (5 micrograms i.c.v.) or reserpine (5 mg/kg i.p.) or the serotonin synthesis inhibitor, p-chlorophenylalanine methyl ester (200 mg/kg i.p. on 2 consecutive days) resulted in a significant decrease in the antinociceptive effect of L-NAME. 4. Similarly, pretreatment with the selective alpha 1-adrenoceptor antagonist prazonin (2.5 mg/kg, i.p.), or the non-selective alpha-adrenoceptor blocker, phentolamine (5 mg/kg, i.p.) antagonized the antinociceptive effect of L-NAME. 5. However, the administration of the selective alpha 2-adrenoceptor antagonist, idazoxan (2.5 mg/kg i.p.) was without effect. 6. Likewise, pretreatment with the serotonin 5-HT2 receptor blocker, ketanserin (1 mg/kg, i.p.), the D2 dopamine receptor antagonist (+/-) sulpiride (30 mg/kg, i.p.) or the opioid antagonist naloxone (5 mg/kg, i.p.) did not inhibit the antinociceptive effect of L-NAME. 7. These results suggest that L-NAME produces antinociception in the mouse probably by an action on adrenergic and serotonergic synapses.     

Modification of antinociceptive action of Ukrain by endogenous nitric oxide in the writhing syndrome test in mice

The effects of L-arginine, the physiological precursor of nitric oxide (NO), and inhibitors of NO-synthase on the antinociceptive action of Ukrain (4.75, 9.5, and 19.0 mg/kg i.p.) were investigated using the writhing syndrome test in mice. It was found that L-arginine (0.1 or 1.0 mg/kg i.p.) significantly decreased or enhanced the antinociceptive effect of Ukrain, depending on the combination administered. In addition, the inhibitors of NO-synthase NG-nitro-L-arginine methyl ester (L-NAME) (1.0 and 10 mg/kg i.p.), 7-nitroindazole (1.0 mg/kg i.p.) and NG-monomethyl-L-arginine acetate (L-NMMA) (1.0 mg/kg i.p.) significantly enhanced Ukrain-induced antinociception. These results suggest that endogenous NO can modify the antinociceptive effect of Ukrain.     

Corticosteroid effects on morphine-induced antinociception as a function of two types of corticosteroid receptors in brain

The antinociceptive effect of parenterally and intracerebroventricularly injected morphine and beta-endorphin in adrenalectomized rats and in adrenalectomized rats treated with adrenal steroids was examined employing the hot-plate method. (1) Adrenalectomy sensitized the rats to an analgesic effect of morphine and beta-endorphin. (2) Replacement therapy (chronic and acute) with corticosterone, dexamethasone or RU 28362 (glucocorticoid receptor agonist) effectively reversed the increase in the sensitivity to the analgesic effect of peripherally injected morphine (5 mg/kg i.p.) induced by adrenalectomy to the level of sham-operated animals. Glucocorticosteroids administered to non-adrenalectomized rats did not change the sensitivity to morphine. (3) Corticosterone had a biphasic, dose-dependent effect; the most significant attenuation of the hypersensitivity to morphine-induced antinociception in adrenalectomized rats was achieved after 0.01 mg and after 10 mg (per kg b.w.). Doses of corticosterone of 0.005 mg/kg and in a range of 0.05-0.30 mg/kg were ineffective. (4) Corticosterone in a dose of 0.01 mg/kg (s.c.) had suppressant effects on the adrenalectomy-induced increase in the sensitivity to antinociception induced by morphine when given prior to morphine (60, 30 and 5 min) as well as after the injection of morphine (before the first and the second testing on the hot-plate, 15 and 5 min, respectively). (5) Intracerebroventricularly (i.c.v.) injected morphine and beta-endorphin also displayed the hypersensitivity to the analgesic effect in adrenalectomized rats which in both cases could be suppressed by 0.01 mg/kg of corticosterone given subcutaneously 5 min prior to administration of the opiate.(ABSTRACT TRUNCATED AT 250 WORDS)     

Antinociceptive effect of amikacin and its interaction with morphine and naloxone.

Amikacin sulphate (30 mg kg(-1)) administered either intraperitoneally (i.p.) or subcutaneously (s.c.) produced antinociceptive effect in BALB/c mice in the acetic acid writhing test which is employed as an inflammatory pain model. The lack of difference between two routes with regard to antinociceptive potency was taken as evidence for the absence of a local effect. Amikacin sulphate-induced antinociception seems unlikely to be due to non-specific behaviour alteration, since this drug, at a dose range of 15-100 mg kg(-1)did not affect motor coordination of mice in rot-a-rod test. Morphine (1 mg kg(-1)) also caused antinociception when administered i.p. or s.c. but the effect was greater with the latter route. At the i.p. site; the concurrent use of amikacin and morphine produced more remarkable antinociception compared to their individual usages. Besides, naloxone (2 mg kg(-1)) significantly decreased antinociceptive effect of amikacin but itself also exerted antinociception. At present, we have no plausible explanation for these findings at the i.p. site.     

Antinociception induced by amitriptyline and imipramine is mediated by alpha2A-adrenoceptors

The involvement of alpha2-adrenoceptors in the antinociception induced by the tricyclic antidepressants amitriptyline and imipramine was investigated in mice by using the hot-plate and abdominal constriction tests. The antinociception produced by amitriptyline (15 mg/kg, i.p.) and imipramine (15 mg/kg, i.p.) was prevented by reserpine (2 mg/kg, i.p.) and yohimbine (3-10 mg/kg, i.p.) but not by naloxone (1 mg/kg, i.p.), atropine (5 mg/kg, i.p.), CGP 35348 (100 mg/kg, i.p.) and prazosin (1 mg/kg, i.p.). On the basis of the above data, it can be postulated that amitriptyline and imipramine exerted their antinociceptive effect by activation of alpha2-adrenoceptors. Administration of the alpha2A-adrenoceptor antagonist BRL 44408 (1 mg/kg, i.p.) prevented amitriptyline and imipramine antinociception, whereas the alpha2B/C-adrenoceptor antagonist ARC 239 (10 mg/kg, i.p.) was ineffective. These data indicate that the enhancement of the pain threshold produced by amitriptyline and imipramine is mediated by activation of alpha2A-adrenoceptors. Neither tricyclic antidepressants nor the antagonists used impaired mouse performance evaluated by the rota-rod and hole-board tests.     

The morphine sparing effect of physostigmine

The antinociceptive effect of morphine was studied in tail-flick- and acetic acid-induced writhing in mice. Morphine effect was dose-related (1, 2 and 5 mg/kg s.c.). Physostigmine (0.05 and 0.1 mg/kg i.p.) potentiated the antinociceptive effect of morphine, and the anticholinergic, scopolamine (1 mg/kg i.p.), reversed the potentiating effect of physostigmine, indicating the involvement of the cholinergic system in pain. Coadministration of physostigmine would increase the therapeutic index of morphine thereby sparing the dose of morphine and also possibly the side effects including the development of tolerance and addiction.     

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.     

Diacerein decreases visceral pain through inhibition of glutamatergic neurotransmission and cytokine signaling in mice

The present study evaluated the antinociceptive effect of the pro-inflammatory cytokines inhibitor diacerein in mice and its possible mechanism of action. The antinociception produced by diacerein was tested at different sites of action, moreover selective antagonists or agonists were used to identify the mechanism that may be involved in its antinociceptive action against acetic acid-induced visceral pain. Diacerein administered systemically (intraperitoneal [i.p.] or intra-gastric [i.g.] routes), supra-spinally (i.c.v.), spinally (i.t.) or peripherally (in association with the irritant agent) inhibited the visceral nociception induced by acetic acid in mice. Interestingly, diacerein treatment (25 mg/kg, i.p. or 50 mg/kg, i.g.) produced long-lasting (for up to 4 h) inhibition of acetic acid-induced nociception. Intraperitoneal treatment of mice with diacerein (25.0 mg/kg) inhibited somatic nociception induced by i.t. injection of glutamate, NMDA, kainate, and trans-ACPD but not that caused by AMPA. Diacerein (5.0-25.0 mg/kg) also produced dose related inhibition of interleukin-1β (IL-1β) and tumor necrosis factor alpha (TNF-α) induced nociception. These results indicate that diacerein produces antinociception by inhibiting glutamatergic transmission through both ionotropic and metabotropic receptors as well as activity of pro-inflammatory cytokines.     

Dopamine D(2) receptor antagonists prevent delta(9)-tetrahydrocannabinol-induced antinociception in rats

Delta(9)-Tetrahydrocannabinol (1 and 5 mg/kg, i.p.) produced, dose-dependently, antinociceptive effects using hot plate and tail flick tests in rats. These effects were suppressed not only by the cannabinoid CB(1) receptor antagonist SR 141716A (0.5 mg/kg; i.p.) but also by the dopamine D(2) receptor antagonists S(-)-sulpiride (5 and 10 mg/kg; i.p.) and S(-)-raclopride (1.5 and 3 mg/kg; i.p.). Conversely, Delta(9)-tetrahydrocannabinol antinociceptive effects were potentiated by the dopamine D(2) receptor agonists (-)-quinpirole (0.025 mg/kg, s.c.) and (+)-bromocriptine (0.5 and 1 mg/kg; i.p.). Our results indicate that the antinociceptive effects of Delta(9)-tetrahydrocannabinol are mediated by the concomitant activation of cannabinoid CB(1) and dopamine D(2) receptors and that dopamine D(2) receptor agonists may be useful in improving the analgesic effects of cannabinoids.