Effects of single and long-term theophylline treatment on the threshold of mechanical nociception: contribution of adenosine A1 and alpha2-adrenoceptors

The effects of single and long-term treatment with theophylline as well as the influence of adenosine A1 receptor agonist cyclopentyladenosine (CPA) and a-adrenergic receptor antagonists prazosin and yohimbine were assessed in the paw pressure test in rats. Both single (37.5 and 75 mg/kg) and long-term (75 mg/kg/day, 14 days i.p.) theophylline treatments exerted antinociceptive effect by increasing the mechanical pain threshold. Single treatment of theophylline (75 mg/kg) antagonized the antinociceptive effect of CPA (0.1 mg/kg); CPA (0.1 mg/kg) abolished the theophylline-induced antinociception. Chronic treatment with theophylline did not change the antinociceptive effect of CPA, while CPA decreased the theophylline antinociception. Yohimbine (0.5 mg/kg), an a 2-adrenoceptor antagonist, diminished the antinociception of a single dose (75 mg/kg) of theophylline, whereas prazocin, an a 1-adrenoceptor antagonist, did not affect it. These results suggest that adenosine A1 and a 2-adrenoceptors take part in the antinociception induced by a single dose of theophylline. The antinociception induced by chronic theophylline treatment probably has a more complex mechanism in which the involvement of adenosine A1.     

Potentiation of adenosine A1 receptor agonist CPA-induced antinociception by paeoniflorin in mice

The effect of paeoniflorin (PF), a major constituent isolated from Paeony radix, on N6-Cyclopentyladenosine (CPA), a selective adenosine A1 receptor (A1 receptor) agonist, induced antinociception was examined in mice. In the tail-pressure test, CPA (0.05, 0.1, 0.2 mg/kg, s.c.) could induce antinociception in a dose-dependent manner. PF (5, 10, 20 mg/kg, s.c.) alone failed to exhibit any antinociceptive effect in mice; however, pretreatment of PF (20 mg/kg, s.c.) could significantly enhance CPA-induced antinociception. Additionally, pretreatment of 8-Cyclopentyl-1,3-dipropylxanthine (DPCPX, 0.25 mg/kg, s.c.), a selective A1 receptor antagonist, could antagonize the antinociceptive effect of combining CPA with PF. Furthermore, in the competitive binding experiments, PF did not displace the binding of [3H]-8-Cyclopentyl-1,3-dipropylxanthine ([3H]-DPCPX) but displaced that of [3H]-2-Chloro-N6-cyclopentyladenosine ([3H]-CCPA, a selective A1 receptor agonist) to the membrane preparation of rat cerebral cortex. These results suggested that PF might selectively increase the binding and antinociceptive effect of CPA by binding with A1 receptor.     

Interaction of angiotensin II and adenosine A1 and A2A receptor ligands on the writhing test in mice

The effects of adenosine A1 and A2A receptor agonists and antagonists administered intraperitoneally (i.p.) and their interaction with angiotensin II (Ang II) administered intracerebroventricularly (i.c.v.) were studied in mice using the acetic acid-induced abdominal constriction test. Ang II (0.1 microg/mouse) induced antinociception in this model. The adenosine A1 receptor agonist N6-cyclopentyladenosine (CPA; 0.05, 0.25 and 0.5 mg/kg) also showed a well-developed antinociceptive effect. Ang II (0.1 microg/mouse) administered 5 min before CPA (0.25 mg/kg) decreased the number of writhes, i.e., it enhanced the antinociceptive effect of CPA. Losartan, an AT1 receptor antagonist (25 microg/mouse i.c.v.), enhanced the antinociceptive effect of CPA, while the AT2 receptor antagonist 1-[-4-(dimethylamino)-3-methylphenylmethyl]-5-diphenylacetyl)-4,5,6,7-tetrahydro 1H-4-imidazol [4,5c]pyridine-6 carboxylic acid, ditrifluoroacetate, dihydrate (PD 123319; 10 microg/mouse) had less effect. 8-Cyclopentyl-1,3-dipropylxanthine (DPCPX; 0.1 mg/kg), an adenosine A1 receptor antagonist, exhibited a pronociceptive effect and did not change the antinociceptive effect of Ang II. The adenosine A2A receptor agonist PD-125944 (DPMA; 0.1, 0.5 and 1 mg/kg) showed pronounced antinociceptive effect. Ang II (0.1 microg/mouse) did not significantly influence the antinociceptive effect of DPMA (0.1 mg/kg). The A2A receptor antagonist 3,7-dimethyl-1-propargilxanthine (DMPX; 0.1 mg/kg) had no effect on the number of writhes and did not influence the effect of Ang II. These data indicate that the antinociceptive effect of Ang II interacts with that produced by adenosine A1 receptor agonist.     

Effect of drugs active at adenosine receptors upon chronic stress-induced hyperalgesia in rats

Hyperalgesia and altered activities of enzymes involved in nucleotide hydrolysis are observed after exposure to repeated restraint in rats. Here, we investigated the effect of an adenosine A(1) receptor agonist, N(6)-cyclopentyladenosine (CPA, 3.35 mg/kg, i.p.), adenosine A(1) receptor antagonist, 1,3-dipropyl-8-cyclopentylxanthine (DPCPX, 0.8 mg/kg, i.p.) as well the effect of an adenosine reuptake blocker, dipyridamole (5 mg/kg, i.p.), on nociception in chronically stressed and control rats. We repeatedly submitted rats to restraint for 40 days. Nociception was assessed with a tail-flick apparatus. The control group presented increased tail-flick latencies after administration of CPA and dipyridamole, but this effect was not observed in the stressed group. DPCPX by itself had no effect on nociception. The analgesic effect of CPA and dipyridamole observed in the control group was reverted by DPCPX. These results indicate the involvement of adenosine A(1) receptor in the antinociception observed in control animals and suggest that the pain signaling induced by chronic stress presents a different modulation involving the adenosinergic system.     

The antinociceptive effects of the systemic adenosine A1 receptor agonist CPA in the absence and in the presence of spinal cord sensitization

Adenosine A1 receptor agonists are effective antinociceptive agents in neuropathic and inflammatory pain, though they appear to be weak analgesics in acute nociception. Important discrepancies are observed on the effectiveness and potency of adenosine analogues when comparing different studies, probably due to the use of different ligands, models of antinociception, routes of administration and types of sensitization. We studied the systemic antinociceptive effects of the adenosine A1 receptor agonist N6-cyclopentyladenosine (CPA) in spinal cord neuronal responses from adult male rats in acute nociception and in sensitization due to arthritis and neuropathy. The experiments showed that CPA was effective in the three experimental conditions, with a similar potency in reducing responses to noxious mechanical stimulation (ID50s: 20 +/- 1.2 microg/kg in acute nociception, 18 +/- 1.1 microg/kg in arthritis, 17.4 +/- 2 microg/kg in neuropathy). The phenomenon of wind-up was also dose-dependently reduced by CPA in the three experimental situations although the main action was seen in arthritis. Depression of blood pressure by CPA was not dose-dependent. We conclude that systemic CPA is a potent and effective analgesic in sensitization due to arthritis and neuropathy but also in acute nociception. The effect is independent of the cardiovascular activity and is centrally mediated since wind-up was inhibited.     

The involvement of nitric oxide in the antinociception induced by cyclosporin A in mice

Cyclosporin A (CsA) and other immunophilin-binding agents are known to inactivate neuronal nitric oxide synthase (nNOS). Nitric oxide (NO) is involved in the nociception at the spinal level. We evaluated the effect of acute intraperitoneal (i.p.) administration of CsA on the tail-flick response in mice and the involvement of NO and opioid receptors in this effect. CsA (5, 10, 20 and 50 mg/kg i.p.) induced a significant increase in tail-flick response. Nitric oxide synthase (NOS) inhibitor N(G)-nitro-L-arginine (LNNA; 10, 40 and 80 mg/kg i.p.) significantly potentiated the CsA-induced (5 mg/kg) increase in tail-flick latency (TFL). While NOS substrate L-arginine (100, 200, 400 mg/kg i.p.) inhibited the CsA-induced (20 mg/kg) antinociception completely and in a dose-dependent manner. Concomitant administration of L-NNA and L-arginine blocked the inhibition exerted by the latter on the CsA-induced antinociception. The opioid receptor antagonist naloxone (4 mg/kg i.p.) did not alter the CsA effect. These results indicate that acute administration of CsA induces an antinociceptive effect that involves the L-arginine-NO pathway but is not mediated by opioid receptors.     

Participation of angiotensin II in learning and memory. II. Interactions of angiotensin II with dopaminergic drugs

The effect of angiotensin II (ATII) and of its interactions with dopaminergic drugs injected post-trial on retention in active avoidance tasks in shuttle-box-trained rats were studied. ATII at doses of 0.10 and 0.50 micrograms administered intracerebroventricularly (i.c.v.) immediately after training improved retention. The dopaminergic receptor agonist apomorphine at a dose of 0.10 mg/kg injected intraperitoneally (i.p.) facilitated retention whereas elymoclavine (a dopaminergic agonist) at a dose of 2.5 mg/kg i.p. had no effect. ATII at a dose of 0.10 micrograms i.c.v. administered after apomorphine 0.10 mg/kg or elymoclavine 2.5 mg/kg exerted a stronger retention-facilitating effect. The dopaminergic receptor antagonist haloperidol at a dose of 1 mg/kg i.p. markedly impaired retention. ATII at a dose of 0.50 micrograms administered after haloperidol (1 mg/kg) did not exercise its retention-facilitating effect. It is concluded that the retention facilitating effects of ATII are realized through interactions with brain dopaminergic transmission.     

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.     

Modulation of cholestasis-induced antinociception by CCK receptor agonists and antagonists.

Acute cholestasis is associated with increased activity of the endogenous opioid system. Agonists and antagonists of cholecystokinin (CCK) receptors are known to modulate opioid-induced antinociception. In the present study, the effect of the CCK receptor agonist caerulein and the antagonist proglumide on antinociception induced during acute cholestasis was investigated in rats using the tail-flick test. A significant increase in nociception threshold was observed in bile duct ligated (BDL) rats compared to sham-operated controls that was maximum on day 7 after the operation and decreased thereafter. Proglumide (40 mg/kg, i.p.) did not affect nociception in unoperated and sham-operated animals, but exerted a significant potentiation of antinociception in cholestatic rats in a way similar to its potentiation effect on unoperated morphine-treated (2 mg/kg, s.c.) animals. Caerulein (0.005, 0.001, 0.01 and 0.02 mg/kg, s.c.), which did not change nociception per se or in sham-operated animals, also significantly potentiated the antinociception in BDL rats as well as in morphine-treated unoperated controls. Caerulein-induced potentiation of antinociception in BDL animals was completely reversed by proglumide pretreatment. Our findings show that, in cholestatic animals, modulation of nociception by the CCK system is different from normal subjects and resembles the state observable in morphine-administered subjects.     

Effects of adenosine analogues on apomorphine-induced penile erection in rats

• 1.1. In the present work, the effect of adenosine agonists and antagonists on apomorphine-induced penile erection (PE) has been studied.
• 2.2. Subcutaneous (s.c.) injection of the nonselective D1/D2 dopamine receptor agonist apomorphine (0.05–0.5 mg/kg) induced PE in a biphasic manner. The maximum effect was obtained with 0.1 mg/kg of the drug. The response decreased with increasing doses of apomorphine, from 0.1 to 0.5 mg/kg.
• 3.3. Intraperitoneal (i.p.) injections of adenosine agonists 5′-N-ethylcarboxamidoadenosine (NECA) and N⁶-cyclohexyladenosine (CHA) decreased the response of apomorphine. Apomorphine-induced PE was increased by low doses (25, 50 mg/kg, i.p.) and decreased by high doses (75, 100 mg/kg, i.p.) of the adenosine antagonist theophylline, respectively. Inhibition of PE induced by NECA and CHA was antagonized by 8-PT pretreatment.
• 4.4. Intracerebroventricular (i.c.v.) administration of CHA, NECA, and theophylline produced the same effects as i.p. injections of these agents on PE responses. It is concluded that A-1 and A-2 adenosine receptor activation may inhibit PE induced by dopaminergic mechanism(s), which can be prevented by 8-PT pretreatment.

     

Evidence for adenosine- and serotonin-mediated antihyperalgesic effects of cizolirtine in rats suffering from diabetic neuropathy

Cizolirtine is a novel non-opioid drug which demonstrated antinociceptive activity in numerous pain models in rodents. Yet, its mechanism of action remains unknown. Several lines of evidence support the idea that adenosine (ADO) and serotonin (5-HT) modulate nociceptive signaling. Our study aimed at investigating whether these neuroactive molecules could be implicated in the mechanism of action of cizolirtine. Cizolirtine-induced antihyperalgesia was compared before and after pretreatment with ADO A(1)-A(2A) and 5-HT(1B/1D) receptor ligands in rats rendered diabetic by streptozotocin pretreatment and suffering from neuropathic pain. Cizolirtine alone (30-80 mg/kg, i.p.) significantly increased mechanical nociceptive thresholds. Acute pretreatment with the A(1)-A(2A) receptor antagonist caffeine (5 mg/kg, i.p.) or the 5-HT(1B/1D) receptor antagonist GR-127,935 (3 mg/kg, i.p.) significantly reduced the antihyperalgesic effects of cizolirtine. Conversely, cizolirtine-induced antihyperalgesia was promoted by pretreatment with either the selective A(1) receptor agonist CPA (0.3 mg/kg, i.p.) or the selective 5-HT(1B) receptor agonist CP-94,253 (3mg/kg, i.p.), and this potentiation was totally prevented by acute pretreatment with respective antagonists. Interestingly, A(1) receptor blockade by DPCPX inhibited the promoting effect of CP-94,253 on cizolirtine-induced antihyperalgesia, suggesting that the adenosine A(1)-mediated step takes place downstream the serotonin 5-HT(1B)-mediated step in the neurobiological mechanisms underlying cizolirtine action.     

Antagonistic activity of ascorbic acid (vitamin C) on dopaminergic modulation: apomorphine-induced stereotypic behavior in mice

Among the various neurotransmitter systems implicated in the mechanism of action of ascorbic acid (vitamin C), the relationship between the dopaminergic system and ascorbic acid is not particularly clear. Ascorbic acid is speculated to have an antagonistic effect on dopaminergic modulation. With this background in mind, in the present study we have seen the effect of ascorbic acid per se and in combination with typical and atypical antipsychotic agents against apomorphine-induced stereotypic behavior in mice. Male Laka mice weighing 20-25 g were used in the present study. Apomorphine-induced stereotypic behavior was used as an animal model. Various dopaminergic modulators were used. Ascorbic acid dose-dependently inhibited stereotypic behavior produced by apomorphine in mice. It potentiated the antipsychotic activity of haloperidol (0.1 mg/kg i.p.), a typical antipsychotic agent. When administered along with atypical antipsychotics, clozapine (1-2 mg/kg i.p.), sulpiride (10-20 mg/kg i.p.) and risperidone (0.0025 mg/kg i.p.), ascorbic acid also potentiated their activity. Also when given along with SCH-23390, a selective D(1) antagonist, an additive effect was observed. Ascorbic acid also inhibited the supersensitization response of apomorphine on reserpinization (2 mg/kg i.p.). Interestingly, at a lower dose (100 mg/kg i.p.), ascorbic acid potentiated the dopaminergic activity of apomorphine (0.5 mg/kg) and BHT-920 (0.25 mg/kg i.p.). However, when given concomitantly with SKF-38393, it failed to alter the response of SKF-38393. The data substantiate the hypothesis that ascorbic acid potentiated the activity of typical as well as atypical antipsychotics and that the effect of ascorbic acid on the dopaminergic system is markedly dose dependent; a low dose (100 mg/kg i.p.) potentiated the dopaminergic action while higher doses (400-1,600 mg/kg i.p.) blocked it.     

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.     

Oleanolic Acid, a pentacyclic triterpene attenuates the mustard oil-induced colonic nociception in mice

Many natural terpenoid compounds from plants exhibit antinociceptive property but very few studies have addressed their efficacy in visceral models of nociception. The present study evaluated the antinociceptive potential of oleanolic acid, a pentacyclic triterpene in the mouse model of colonic nociception induced by mustard oil. We further examined the possible participation of opioid, alpha2-adrenergic, and transient receptor potential vanilloid 1 (TRPV1)-receptors in its mechanism. Mice were pretreated orally with oleanolic acid (3, 10, 30 mg/kg) or vehicle, and the pain-related behavioral responses to intracolonic injection of mustard oil was analysed. Oleanolic acid significantly suppressed the mustard oil-induced nociceptive behaviors at test doses of 10 and 30 mg/kg, in a dose-related manner. The antinociceptive effect of oleanolic acid (30 mg/kg) was significantly blocked by pretreatment with the opioid antagonist, naloxone (2 mg/kg, i.p.), while the alpha2-adrenoceptor antagonist, yohimbine (2 mg/kg, s.c.), had no effect. Pretreatment with ruthenium red (3 mg/kg, s.c.), a non-competitive TRPV1 antagonist alone caused significant inhibition of mustard oil-induced nociception but its co-administration with oleanolic acid produced neither antagonism nor potentiation of oleanolic acid antinociception. In the open-field test that detects sedative or motor abnormality, mice received 30 mg/kg oleanolic acid did not show any per se influence, but significantly inhibited the mustard oil-induced decrease in ambulation frequency. These data demonstrate the visceral antinociceptive potential of oleanolic acid that involves an opioid mechanism and possibly a modulatory influence on vanilloid-receptors, which needs further study.     

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.     

Serotonergic mechanism in imipramine induced antinociception in rat tail flick test

Substantial evidence has accumulated that spinally projecting serotonergic neurons modulate nociception. However, the exact receptor subtypes that mediate the antinociceptive response of serotonin within the spinal cord continue to be a subject of debate. Therefore, we explored the effect of serotonergic system on imipramine induced antinociception by using 5-Hydroxytryptamine-3 (5HT3) receptor antagonist ondansetron and 5-Hydroxytryptamine-2 (5HT2) receptor antagonist mianserine, and depletion of brain 5-Hydroxytryptamine (5HT) with p-chlorophenyl alanine (PCPA). Male wistar strain rats were pretreated with either ondansetron (0.5 mg/kg, i.p.) or mianserine (1 mg/kg, i.p.). After 15 minutes, rats received injection of imipramine (10 mg/kg). Nociception was assessed by tail-flick method. Imipramine (2 mg, 5 mg, 10 mg, and 20 mg/kg) produce antinociceptive response in the dose dependent manner. Prior treatment with 5HT3 antagonist, Ondansetron and 5HT2 antagonist, mianserine reduce the antinociceptive response of imipramine. In PCPA treated rats imipramine (10 mg/kg) failed to produce antinociception. These results indicate that the 5HT plays an important role in imipramine induced antinociception.     

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.     

The role of L-arginine/nitric oxide pathway in the antinociceptive activity of pyridoxine in mouse.

In the present study the role of L-arginine/nitric oxide (NO)/cGMP pathway in the antinociceptive activity of pyridoxine in p-benzoquinone-induced abdominal constriction test in mouse was investigated. Pyridoxine (CAS 58-56-0) displayed dose-dependent antinociceptive activity at 0.0625-1 mg/kg (s.c.) doses. L-arginine (CAS 1119-34-2), a NO precursor, displayed a triphasic pattern as antinociception-nociception-antinociception (61.8 +/- 7.8, -36.5 +/- 12.7 and 17.0 +/- 4.3%, 5, 40 and 50 mg/kg, s.c., respectively). The antinociceptive effect of pyridoxine at ED50 dose (0.43 mg/kg, s.c.) (47.7 +/- 3.9%) was significantly decreased by L-arginine at 40 and 50 mg/kg doses (4.1 +/- 9.3 and 37.8 +/- 1.6%, respectively) while 5 mg/kg dose of L-arginine significantly potentiated the pyridoxine analgesia. On the other hand, pyridoxine reversed the L-arginine-induced nociception to antinociception (4.1 +/- 9.3%) and augmented the antinociceptive effect of L-arginine (37.8 +/- 1.6%). L-NG-nitroarginine methyl ester (CAS 51298-62-5), a NO synthase inhibitor, at 75 mg/kg, s.c. produced antinociception and significantly increased the antinociceptive effect of pyridoxine (63.7 +/- 1.2%). Methylene blue (CAS 61-73-4, MB), a guanylyl cyclase and/or NO synthase inhibitor, was antinociceptive and nociceptive at 5 and 40 mg/kg doses, respectively, 5 mg/kg dose of MB significantly increased the antinociceptive effect of pyridoxine, but did not change it at 40 mg/kg dose. On the other hand, pyridoxine significantly decreased the antinociceptive effect of MB and reversed the MB-induced nociception to antinociception. Combination of pyridoxine and morphine (CAS 57-27-2) (ED50: 0.13 mg/kg, s.c.) at 49.8 +/- 1.9% revealed a significant antinociceptive potentiation (69.1 +/- 1.8%). The findings of the present study emphasise the contribution of central and/or peripheral L-arginine/NO/cGMP nociceptive processes in pyridoxine-induced antinociception.     

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.     

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.