Potentiation of imipramine-induced antinociception by nicotine in the formalin test.

In this study, the effect of cholinergic agents on imipramine antinociception in mice, in the formalin test, has been investigated. Intraperitoneal (i.p.) administration of different doses of imipramine (2.5, 5, 10, 20 and 30 mg/kg) or nicotine (0.25, 0.5, 0.75 and 1 mg/kg) induced a dose dependent antinociception in both the first and second phases of the formalin test in mice. The combination of imipramine with doses of 0.5 and 0.75 mg/kg of nicotine showed a potentiated response, in both phases of the test. However, neither hexamethonium (5 and 10 mg/kg), atropine (0.25 mg/kg) or mecamylamine (0.25 mg/kg) altered the antinociception induced by imipramine. It is concluded that nicotinic receptor activation but not the cholinergic muscarinic mechanism is involved in the imipramine-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.     

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.     

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.     

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.     

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.     

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.     

Central effect of histamine and peripheral effect of histidine on the formalin-induced pain response in mice

1. The present study was designed to investigate the role of brain histamine in modulating pain transmission in mice. 2. In conscious mice implanted with an intracerebroventricular (i.c.v.) cannula, the effects of i.v.c. injections of normal saline (control) and low and high doses histamine (2 and 40 microg/mouse, respectively) were investigated on the duration of paw licking and biting induced by subcutaneous (s.c.) injection of formalin (20 microL; 5%) into the plantar surface of the left hindpaw. 3. To clarify the involvement of histidine in the pain response, the effects of intraperitoneal (i.p.) injections of low and high doses of histidine (50 and 1000 mg/kg, respectively) alone or before i.c.v. injection of histamine were also examined. 4. Intraplantar injection of formalin induced a biphasic pain response (first phase: 0-5 min after injection; second phase: 20-40 min after injection). 5. Histamine (2 microg/mouse, i.c.v.) had no effect on the first phase of the pain response, but suppressed the second phase. The higher dose of histamine (40 microg/mouse, i.c.v.) suppressed both phases of the pain response. 6. Histidine, at 50 mg/kg, i.p., had no effect on the pain response, but the higher dose (1000 mg/kg, i.p.) suppressed the both phases of the pain response. 7. Pretreatment with the low dose of histidine (50 mg/kg, i.p.) prior to administration of 2 microg/mouse, i.c.v., histamine did not change the antinociception induced by low-dose histamine. However, pretreatment with the high dose of histidine (1000 mg/kg, i.p.) prior to 2 microg/mouse, i.c.v., histamine produced antinociception that resembled that seen following administration of the high dose of either histidine or histamine. Pretreatment with the low dose of histidine (50 mg/kg, i.p.) prior to administration of 40 microg/mouse, i.c.v., histamine has no effect on the pain response following high-dose histamine. Pretreatment with 1000 mg/kg, i.p., histidine prior to administration of 40 microg/mouse, i.c.v., histamine strongly suppressed both phases of the formalin-induced pain response, particularly the second phase. 8. The results of the present study indicate that: (i) activation of brain histamine produces antinociception in the mouse formalin test; (ii) peripheral loading with a high dose of histidine (1000 mg/kg, i.p.) alone exerts the same effect as that seen following 40 microg/mouse, i.c.v., histamine; and (iii) pretreatment with a high dose of histidine potentiates central histamine-induced antinociception.     

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).     

Antinociceptive effect of the monoterpene R-(+)-limonene in mice

In the present study were studied the antinociceptives properties of monoterpene R-(+)-limonene (LM) in chemical and thermal models of nociception in mice. The R-(+)-limonene was administered, intraperitoneally (i.p.), at doses of 25 and 50 mg/kg. The results showed significant inhibition produced on chemical nociception induced by intraperitoneal acetic-acid and in the second phase of subplantar formalin test, but did not manifest a significant effect in hot-plate test. The R-(+)-limonene-induced antinociception in second phase of formalin test was insensitive to naloxone (1 mg/kg, s.c.). It was also demonstrated that R-(+)-limonene (25, 50 mg/kg) neither significantly enhanced the pentobarbital-sleeping time nor impaired the motor performance in rota-rod test, indicating that the observed antinociception is unlikely to be due to sedation or motor abnormality. In conclusion it may be suggested that the R-(+)-limonene presented antinociceptive activity and that, probably, this action can be related with peripheral analgesia, but, not with the stimulation of opioids receptors.     

Clonidine and guanfacine-induced antinociception in visceral pain: possible role of alpha 2/I2 binding sites

Visceral pain is one of the most common forms of pain which is poorly understood. We now studied the influence of imidazoline/guanidinium compounds such as clonidine and guanfacine on visceral pain in the presence or absence of yohimbine and benazoline. To produce visceral pain-related behaviours, formalin (10%) was administered by inserting a fine cannula into the colon via the anus. Each experiment took 1 h. Clonidine (0.001, 0.01 and 0.1 mg/kg, i.p.) and guanfacine (2.5, 5 and 10 mg/kg, i.p.) produced analgesia dose dependently. The clonidine response was inhibited by yohimbine (0.2 mg/kg, i.p.). On the other hand, benazoline (5 mg/kg, i.p.) blocked the antinociceptive effect of guanfacine (5 mg/kg). Benazoline (2.5 and 5 mg/kg) itself also induced analgesia in inflammatory colonic pain. In this study, we used morphine to ensure that the behavioural responses were pain-related. Our results showed that morphine (2.5, 5 and 10 mg/kg, s.c.) produced a dose-dependent antinociception. The morphine (7 mg/kg, s.c.) response was reduced by naloxone (2 mg/kg, i.p.). However, we concluded that both imidazoline (I(2)) and alpha(2)-adrenoceptors may play a role in producing analgesia in visceral pain.     

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.     

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.     

GABAA-antagonists and baclofen analgesia

1. Intraperitoneal (i.p.) injection of different doses of baclofen (5, 7.5 and 10 mg/kg) induced analgesia in tail-flick test. The effect was dose-dependent. 2. The antinociception induced by baclofen (10 mg/kg, i.p.) was decreased in animals pretreated with bicuculline (1.5 mg/kg, i.p., 30 min), but not with naloxone (1.5 mg/kg, i.p., 30 min). 3. In picrotoxin (1 mg/kg, i.p., 15 min) pretreated mice, baclofen (5 mg/kg, i.p.) showed a significant analgesic effect. 4. Morphine (6 mg/kg, s.c.) induced analgesia which was antagonized by naloxone pretreatment (1.5 mg/kg, i.p.), while bicuculline or picrotoxin did not alter the morphine response. 5. These data suggest that a part of analgesic effect of baclofen may be mediated through GABAA receptor sites, and differs from that of morphine.     

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     

Influence of ACTH on the effects of imipramine, desipramine and lithium on duration of immobility of rats in the forced swim test.

We examined the effects of adrenocorticotropic hormone (ACTH) on the immobilization of rats in the forced swim test with the administration of imipramine, desipramine, or lithium. A single administration of either imipramine (10-30 mg/kg, i.p.) or desipramine (30 mg/kg, i.p.) significantly decreased the duration of immobility in normal rats in a dose-dependent manner. Lithium (10-100 mg/kg, p.o.), however, had no affect on the performance of rats in the forced swim test. ACTH (100 microg/day), administered subcutaneously to rats for 1, 3, 7, and 14 days, had no apparent effect on the duration of immobility in this test. The immobility-decreasing effect induced by a single administration of either imipramine (10-30 mg/kg, i.p.) or desipramine (30 mg/kg, i.p.) was blocked by chronic administration of ACTH for 3-14 days. The reduction of immobility, induced by chronic administration of imipramine (10 mg/kg, i.p.) for 15 days, was blocked by treatment with ACTH for 14 days. When lithium (100 mg/kg, p.o.) was administered for 15 days concurrently with imipramine (10 mg/kg, i.p.), we observed a significant decrease in immobility in rats treated with ACTH for 14 days. We suggest that chronic treatment of rats with ACTH may prove to be an effective model of tricyclic antidepressants-treatment-resistant depression.     

Effect of chronic and acute administration of fluoxetine and its additive effect with morphine on the behavioural response in the formalin test in rats

Serotonergic systems are involved in the central regulation of nociceptive sensitivity. Fluoxetine, a selective inhibitor of the reuptake of serotonin (5-hydroxytryptamine, 5-HT), was administered orally (0.16, 0.32, 0.8 mg kg(-1) daily for 7 days), intraperitoneally (0.04, 0.08, 0.16 mg kg(-1) day(-1) for 7 days and a single dose of 0.32 mg kg(-1)) and intracerebroventricularly (10 microg/rat) to rats and nociceptive sensitivity was evaluated using the formalin test (50 microL of 2.5% formalin injected subcutaneously). The effect of fluoxetine was also studied in the presence of 5,7-dihydroxytryptamine creatinine sulfate (5,7-DHT) and after co-administration with morphine. Oral (0.8 mg kg(-1)), intraperitoneal (0.16 and 0.32 mg kg(-1)) and intracerebroventricular (10 microg/rat) fluoxetine induced antinociception in the late phase of the formalin test. Furthermore, intrathecal administration of 5-HT (100 microg/rat) induced an analgesic effect. The analgesic effect of fluoxetine (0.16 and 0.32 mg kg(-1), i.p.) and 5-HT (100 microg/rat, i.t.) was abolished by pre-treatment with 5,7-DHT (100 microg/rat, i.t.). In addition, the analgesic effect of 5-HT (100 microg/rat, i.t.) was decreased by pre-treatment with naloxone (2 mg kg(-1), i.p.). Morphine (5 mg kg(-1), i.p.) induced analgesia that was increased by fluoxetine (0.32 mg kg(-1), i.p.). These results suggest that fluoxetine has an antinociceptive effect in tonic inflammatory pain through functional alteration of the serotonergic system and also potentiates the analgesic effect of morphine.     

Endogenous opioid mechanisms partially mediate P2X3/P2X2/3-related antinociception in rat models of inflammatory and chemogenic pain but not neuropathic pain

P2X3/P2X2/3 receptors have emerged as important components of nociception. However, there is limited information regarding the neurochemical systems that are affected by antagonism of the P2X3/P2X2/3 receptor and that ultimately contribute to the ensuing antinociception. In order to determine if the endogenous opioid system is involved in this antinociception, naloxone was administered just prior to the injection of a selective P2X3/P2X2/3 receptor antagonist, A-317491, in rat models of neuropathic, chemogenic, and inflammatory pain. Naloxone (1-10 mg kg(-1), i.p.), dose-dependently reduced the antinociceptive effects of A-317491 (1-300 micromol kg(-1), s.c.) in the CFA model of thermal hyperalgesia and the formalin model of chemogenic pain (2nd phase), but not in the L5-L6 spinal nerve ligation model of neuropathic allodynia. In comparison experiments, the same doses of naloxone blocked or attenuated the actions of morphine (2 or 8 mg kg(-1), s.c.) in each of these behavioral models. Injection of a peripheral opioid antagonist, naloxone methiodide (10 mg kg(-1), i.p.), did not affect A-317491-induced antinociception in the CFA and formalin assays, suggesting that the opioid component of this antinociception occurred within the CNS. Furthermore, this utilization of the central opioid system could be initiated by antagonism of spinal P2X3/P2X2/3 receptors since the antinociceptive actions of intrathecally delivered A-317491 (30 nmol) in the formalin model were reduced by both intrathecally (10-50 nmol) and systemically (10 mg kg(-1), i.p.) administered naloxone. This utilization of the opioid system was not specific to A-317491 since suramin-, a nonselective P2X receptor antagonist, induced antinociception was also attenuated by naloxone. In in vitro studies, A-317491 (3-100 microM) did not produce any agonist response at delta opioid receptors expressed in NG108-15 cells. A-317491 had been previously shown to be inactive at the kappa and mu opioid receptors. Furthermore, naloxone, at concentrations up to 1 mM, did not compete for [3H] A-317491 binding in 1321N1 cells expressing human P2X3 receptors. Taken together, these results indicate that antagonism of spinal P2X3/P2X2/3 receptors results in an indirect activation of the opioid system to alleviate inflammatory hyperalgesia and chemogenic nociception.     

Acute effect of essential oil of Eugenia caryophyllata on cognition and pain in mice

The essential oil of Eugenia caryophyllata (clove oil; Family: Myrtaceae) is used in dental care as an antiseptic and analgesic. The study aims to evaluate the effect of clove oil on experimental models of pain and cognition in mice. To observe the acute effects of clove oil at different doses, the elevated plus maze was used for the assessment of cognition, and the tail flick and formalin tests were used for the study of pain. The formalin test showed that clove oil (0.1?ml/kg, i.p.) demonstrated significantly reduced pain response in both the phases. The lower doses (0.025 and 0.05?ml/kg, i.p.) reduced the formalin-induced pain response significantly in the second phase only. The tail-flick test showed variable response. The dose 0.1?ml/kg, clove oil, significantly decreased the tail-flick latency at 30?min and this effect was reversed by naloxone (1?mg/kg). On the contrary, the dose 0.025?ml/kg of clove oil, at 30 and 60?min increased the mean tail-flick latency compared to control group, but this effect was not statistically significant. Yet naloxone significantly (p?相似文献