2-Deoxy-D-glucose antinociception and serotonin receptor subtype antagonists: test-specific effects in rats.

The antinociceptive actions of 2-deoxy-D-glucose (2-DG) are mediated in part by endogenous opioid, dopaminergic, cholinergic, histaminergic, and neurohormonal influences. Although 2-DG antinociception was not affected by tryptophan hydroxylase inhibition, a possible serotonergic role in 2-DG antinociception was investigated because of the existence of serotonin [5-hydroxytryptamine (5-HT)] receptor subtypes. The present study examined the effects of general (methysergide: 5 and 10 mg/kg), 5-HT2 (ritanserin: 2.5 mg/kg), and 5-HT3 (ICS-205,930: 0.25-5 mg/kg) receptor subtype antagonists upon 2-DG antinociception on the tail-flick and jump tests in rats. On the tail-flick test, 2-DG (450 mg/kg) antinociception was significantly reduced by all ICS-205,930 doses (48-58%) but unaffected by either methysergide (22-29% reduction) or ritanserin (6% reduction). In contrast, 2-DG antinociception on the jump test was significantly potentiated across the 120-min time course and across the 2-DG dose-response curve (100-650 mg/kg) by methysergide, ritanserin, and ICS-205,930 pretreatment. Each of the three antagonists produced significant leftward shifts in the peak and total 2-DG dose-response curve for the jump test. These data suggest different sites of action for 2-DG antinociception as a function of the pain test employed and a differential modulation by serotonin receptor subtypes at those sites.     

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.     

MD-354 potentiates the antinociceptive effect of clonidine in the mouse tail-flick but not hot-plate assay

Albeit conflicting, evidence suggests that 5-HT3 receptor partial agonists as well as alpha2NON-A-adrenoceptor agonists might be involved in antinociception. MD-354 (m-chlorophenylguanidine) can be viewed as the first example of a rather selective 5-HT3/alpha2B-adrenergic ligand. In a tail-flick test in mice, subcutaneous administration of MD-354 doses up to 30 mg/kg did not produce antinociception and failed to antagonize the effect of clonidine (ED50=0.5 mg/kg), but a combination of an inactive de of clonidine (0.25 mg/kg) that produced only 13% maximal possible effect (MPE) with an inactive dose of MD-354 (10 mg/kg, MPE=8%) produced an antinociceptive effect (MPE=83%). In the hot-plate assay, neither subcutaneous administration of MD-354 (3 to 30 mg/kg) alone nor in combination with clonidine (ED50=0.8 mg/kg) produced an antinociceptive effect. MD-354 was demonstrated to potentiate the antinociceptive effect of clonidine in the tail-flick assay, but its underlying mechanism remains to be determined.     

Naltrexone, serotonin receptor subtype antagonists, and glucoprivic intake: 1. 2-Deoxy-D-glucose.

Inhibition of deprivation-induced intake by naloxone was significantly enhanced by the 5-hydroxytryptamine3 (5-HT3) antagonist ICS-205,930. Interactions between naloxone and either the general 5-HT antagonist methysergide or the 5-HT2 antagonist ritanserin or ketanserin produced smaller effects. The present study evaluated whether 2-deoxy-D-glucose (2DG, 400 mg/kg) hyperphagia was affected by methysergide (0.5-5 mg/kg), ritanserin (0.25-2.5 mg/kg), or ICS-205,930 (0.5-5 mg/kg) alone or in combination with naltrexone (0.25 and 2.5 mg/kg). Only ICS-205,930 stimulated spontaneous intake for up to 4 h in the light cycle. Only ritanserin (1.25 mg/kg) transiently reduced 2DG hyperphagia. The dose-dependent decreases in 2DG hyperphagia by naltrexone were significantly enhanced by the dose range of ICS-205,930. The inhibition of 2DG hyperphagia by the low naltrexone dose was enhanced by methysergide (5 mg/kg) and ritanserin (1.25 mg/kg). These data suggest that the 5-HT3 receptor primarily interacts with opioid systems to modulate 2DG hyperphagia and that one possible locus of interaction is in the caudal brainstem.     

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.     

Antinociceptive evaluation of 14β-(bromoacetamido)- 7,8-dihydro-N(cyclopropylmethyl)-normorphinone in mice

This study evaluated the supraspinal opioid effects of 14β-(bromoacetamido)-7,8-dihydro-N(cyclopropylmethyl)-normorphinone (N-CPM-H₂BAMO) in the mouse acetic acid-induced writhing and tail-flick assays. In the writhing test, N-CPM-H₂BAMO produced a time- and dose-dependent antinociception after i.c.v. administration, with a 50% antinociceptive response being obtained with 0.28 (0.19–0.39) nmol when given 10 min before testing. The antinociceptive effect of N-CPM-H₂BAMO was antagonized in a dose-dependent manner by the κ-selective opioid receptor antagonist, nor-binaltorphimine. In the mouse tail-flick assay, N-CPM-H₂BAMO failed to produce any antinociception after i.c.v. administration. N-CPM-H₂BAMO produced a dose-dependent antagonism of morphine-induced antinociception but not antinociception induced by the δ-opioid receptor agonist [D-Pen²,D-Pen⁵]enkephalin. Nor-binaltorphimine (0.3 nmol) at dose that completely antagonized N-CPM-H₂BAMO-induced antinociception in the writhing assay did not prevent the antagonistic effect of N-CPM-H₂BAMO on morphine-induced antinociception. Therefore, these data indicate that N-CPM-H₂BAMO produces antinociception by acting at supraspinal κ-opioid receptors in the writhing assay, and also acts as a μ-opioid receptor antagonist.     

The atypical neuroleptics clozapine and olanzapine differ regarding their antinociceptive mechanisms and potency.

Using the mouse tail-flick assay, we evaluated the antinociceptive effect and the interaction with the opioid, adrenergic, and serotonergic systems of the two "atypical" neuroleptic agents clozapine and olanzapine. Clozapine induced a potent antinociceptive effect in a dose-dependent manner with ED50 of 8.7 mg/kg. This effect was antagonized by the nonselective opioid antagonist naloxone (p < 0.05), implying an opioid mechanism of action involved in clozapine-induced antinociception. Further evaluation demonstrated the involvement of micro1-, micro2-, kappa1- opioid receptor subtypes and of alpha2-adrenoreceptors in clozapine antinociception but not the serotonin receptors. Olanzapine induced a weak antinociceptive effect. The highest effect found was a 50% antinociception following an injection of 10 mg/kg. As the olanzapine dose increased beyond 10 mg/kg, latencies declined almost back to baseline. Yohimbine (an alpha2-adrenoreceptor antagonist) significantly reduced olanzapine's antinociceptive effect almost completely (to 10%; p < 0.05), while both naloxone and metergoline (a nonselective 5-HT receptor antagonist) reduced it only partially. These results indicate the possible involvement of the alpha2-adrenoreceptors in olanzapine antinociception and to a less extent the involvement of opioid and serotonergic receptors. Although both clozapine and olanzapine are dibenzodiazepines with similar "atypical" antipsychotic properties, it seems that they differ notably not only regarding their hematological side effects, but regarding their interaction with the opioid system as well.     

Further study on the effects of histamine H2 receptor agonist and antagonists on restraint-induced antinociception in mice.

In previous studies, histamine was shown to affect the antinociceptive activity induced by stress in mice. The present work was carried out to further examine the role of histamine in this phenomenon. Restraint for 1 h induced significant antinociceptive activity as assessed by the hot plate test in both male and female mice. The antinociceptive activity was enhanced by prior administration of the histamine H2 receptor agonist dimaprit (6.0 mg/kg s.c.) 15 min before restraint. Furthermore, the induction of antinociceptive activity by restraint was antagonized by prior administration of histamine H2 receptor antagonists (10.0 mg/kg s.c.), cimetidine or zolantidine. In the male mice, naloxone (4.0 mg/kg s.c.) administered 10 min before or immediately after restraint did not affect the antinociception induced by restraint. In addition, the potentiating effect of dimaprit and the inhibitory effect of cimetidine and zolantidine were not affected by administration of naloxone. However, in female mice, naloxone given 10 min before restraint completely abolished the induction of antinociceptive activity by restraint and the effects of histamine H2 receptor agonist and antagonists on restraint induced antinociception were not observed. Moreover, the antinociceptive activity induced by restraint and the dimaprit-induced potentiation of antinociceptive activity were diminished by naloxone administered immediately after the restraint. The present findings further support our previous studies which suggested that the histamine H2 receptor most probably is involved in enhancing the intensity of stress in restraint-induced antinociception thus altering the degree of antinociception observed.     

Systemic morphine produce antinociception mediated by spinal 5-HT7, but not 5-HT1A and 5-HT2 receptors in the spinal cord

BACKGROUND AND PURPOSE: The serotonergic system within the spinal cord have been proposed to play an important role in the analgesic effects of systemic morphine. Currently, seven groups of 5-HT receptors (5-HT1-7) have been characterized. One of the most recently identified subtypes of 5 HT receptor is the 5-HT7 receptor. We aimed to examine the role of spinal 5-HT7 receptors in the antinociceptive effects of systemic morphine. EXPERIMENTAL APPROACH: The involvement of spinal 5-HT7 receptor in systemic morphine antinociception was compared to that of the 5-HT1A and 5-HT2 receptors by using the selective 5-HT7 receptor antagonist, SB-269970, the selective 5-HT1A receptor antagonist, WAY 100635, the selective 5-HT2 antagonist ketanserin as well as the non-selective 5-HT1,2,7 receptor antagonist, metergoline. Nociception was evaluated by the radiant heat tail-flick test. KEY RESULTS: I.t. administration of SB-269970 (10 microg) and metergoline (20 microg) completely blocked the s.c. administered morphine-induced (1, 3, 5 and 10 mg kg(-1)) antinociception in a time-dependent manner. Additionally, i.t. administration of SB-269970 (1, 3, 10 and 20 microg) and metergoline (1, 5, 10 and 20 microg) dose dependently inhibited the antinociceptive effects of a maximal dose of morphine (10 mg kg(-1), s.c.). I.t. administration of WAY 100635 (20 microg) or ketanserine (20 microg) did not alter morphine-induced (1, 3, 5 and 10 mg kg(-1), s.c.) antinociception. CONCLUSION AND IMPLICATIONS: These findings indicate that the involvement of spinal 5-HT7, but not of 5-HT1A or of 5-HT2 receptors in the antinociceptive effects of systemic morphine.     

Effects of muscarinic receptor antagonism upon two forms of stress-induced analgesia

The present study assessed in rats the effects of muscarinic receptor antagonism upon analgesia induced by cold-water swims (CWS: 2 degrees C for 3.5 min) and 2-deoxy-D-glucose (2DG: 600 mg/kg). First, CWS analgesia was significantly reduced 30 min after the swim by scopolamine (0.01 and 0.1 mg/kg) and methylscopolamine (10 mg/kg) pretreatment, and was eliminated 60 min after the swim by scopolamine (0.01-10 mg/kg) and methylscopolamine (1,10 mg/kg) pretreatment. In contrast, scopolamine potentiated CWS hypothermia. Second, while scopolamine (1 mg/kg) and methylscopolamine (1,10 mg/kg) pretreatment prolonged 2DG analgesia, both antagonists dose-dependently reduced 2DG hyperphagia. Third, the changes in analgesic and hypothermic stress responses were not due to baseline shifts in jump thresholds or body temperatures. However the dose-dependent reductions by scopolamine and methylscopolamine in baseline food intake and 2DG hyperphagia were significantly correlated. Fourth, the dose-dependent reduction by scopolamine and methylscopolamine of pilocarpine analgesia differed in pattern from the other analgesic effects, suggesting heterogeneity in muscarinic receptor modulation of different analgesic responses.     

Dopamine receptor mechanism(s) and morphine tolerance in mice

Based on our previous demonstration of the involvement of dopamine-2 (D2) dopamine receptors in morphine antinociception, we examined the role of D2 dopamine receptors in the expression and development of tolerance to morphine antinociception in mice. Tolerance to morphine antinociception was assessed by the tail-flick response after the administration of morphine (50 mg/kg) once daily for 3 days. The D2 dopamine receptor agonist, quinpirole (0.01, 0.02 and 0.03 mg/kg), but not the D2 dopamine receptor antagonist, sulpiride (12.5, 25 and 50 mg/kg), increased morphine antinociception in morphine non pre-exposed mice. The response of quinpirole was decreased by the lower doses of sulpiride. Both quinpirole and sulpiride decreased the expression and development of tolerance to antinociception induced by morphine (1.5, 3 and 6 mg/kg). The effect of quinpirole on the expression and development of tolerance, was reduced by a lower and per se non-effective dose of sulpiride. It was concluded that D2 dopaminergic receptors may play a part in the expression and development of tolerance to the antinociceptive effect of morphine.     

N-Methyl-D-aspartate receptor modulators block hyperalgesia induced by acute low-dose morphine

1. Following opioid-induced antinociception in mice, hyperalgesic responses may be observed. The present study was designed to evaluate the effect of different N-methyl-d-aspartate (NMDA) receptor modulators (magnesium, dextromethorphan, d-serine) on the development of morphine-induced hyperalgesia in mice. The tail-flick test was used to assess the effects of morphine alone and in combination with the NMDA receptor modulators. 2. Administration of a single low dose (2 mg/kg) of morphine to mice produced antinociception that was followed by hyperalgesia. 3. Administration of magnesium sulphate (5 mg/kg) and d-serine (10 mg/kg) alone produced a transient antinociceptive response, whereas dextromethorphan (10 mg/kg) alone produced a prolonged antinociceptive response that had a relatively delayed onset after 4 h. 4. When coadministered with morphine, the NMDA receptor blockers magnesium (2 mg/kg) and dextromethorphan (2 and 5 mg/kg) and the NMDA receptor agonist d-serine (2, 5 and 10 mg/kg), maintained the duration of the antinociceptive response to morphine and inhibited the development of the hyperalgesic response. Coadministration of dextromethorphan (10 mg/kg) with morphine produced antinociception at 30-120 min and at 4-24 h. 5. The results of the present study suggest that coadministration of low-dose NMDA receptor antagonists, as well as the NMDA receptor agonist d-serine, with morphine can inhibit morphine-induced hyperalgesia.     

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.     

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.     

The antinociceptive effects of endomorphin-1 and endomorphin-2 in diabetic mice

The antinociceptive effects of endomorphin-1 and endomorphin-2, endogenous mu-opioid receptor agonists, were examined using the tail-flick test in non-diabetic and diabetic mice. Endomorphin-1, at doses of 1 to 10 microg, i.c.v., and endomorphin-2, at doses of 3 to 30 microg, i.c.v., each dose dependently inhibited the tail-flick response in both non-diabetic and diabetic mice. There was no significant difference between the antinociceptive effects of endomorphin-1 in non-diabetic mice and diabetic mice. The antinociceptive effect of endomorphin-2 was greater in non-diabetic mice than in diabetic mice. In non-diabetic mice, the antinociceptive effects of endomorphin-1 and endomorphin-2 were significantly reduced by beta-funaltrexamine, a mu-opioid receptor antagonist, and naloxonazine, a selective mu(1)-opioid receptor antagonist, but not by naltrindole, a delta-opioid receptor antagonist, or nor-binaltorphimine, a kappa-opioid receptor antagonist. In diabetic mice, the antinociceptive effect of endomorphin-2 was significantly reduced by beta-funaltrexamine and naloxonazine. However, these micro-opioid receptor antagonists had no significant effect on the antinociceptive effect of endomorphin-1 in diabetic mice. The antinociception induced by endomorphin-1 in diabetic mice was significantly reduced by naltrindole and 7-benzylidenenaltrexon, a selective delta(1)-opioid receptor antagonist, administered i.c.v. However, nor-binaltorphimine had no significant effect on the antinociceptive effects of endomorphin-1 and endomorphin-2 in diabetic mice. These results indicate that the antinociceptive effects of endomorphin-1 and endomorphin-2 in non-diabetic mice are mediated through the activation of mu(1)-opioid receptors, whereas in diabetic mice, endomorphin-1 and endomorphin-2 may produce antinociception through different actions at delta(1)- and mu(1)-opioid receptors, respectively.     

Clonidine-induced antinociception and locomotor hypoactivity are reduced by dexamethasone in mice

The effects of dexamethasone pretreatment on clonidine-induced antinociception and locomotor hypoactivity were investigated in mice. In the hot-plate and the tail-flick tests, dexamethasone administered intraperitoneally at a dose of 1 mg kg(-1), 30 or 60 min before clonidine, reduced clonidine antinociception in both tests and reduced clonidine-induced locomotor hypoactivity in the activity cage. When administered 15 min before clonidine, dexamethasone had no effect on clonidine antinociception. A higher dexamethasone dose (10 mg kg(-1)) induced the same effects observed at a dose of 1 mg kg(-1) in the hot-plate and the tail-flick tests, but the former dose had a stronger effect on locomotor hypoactivity. Dexamethasone (10 ng/mouse) administered intracerebroventricularly 30 min before clonidine was also able to reduce both clonidine-induced antinociception and locomotor hypoactivity. The protein synthesis inhibitor, cycloheximide, administered intraperitoneally at the dose of 10 mg kg(-1), 2 h before clonidine, was able to prevent dexamethasone effects on clonidine-induced antinociception. The glucocorticoid receptor antagonist RU-38486, administered intracerebroventricularly at the dose of 1 ng/mouse, was also able to block dexamethasone effects on clonidine-induced antinociception and locomotor hypoactivity, whereas both cycloheximide and RU-38486 per se did not influence pain sensitivity or locomotor activity. These results suggest that the dexamethasone effects on clonidine-induced antinociception and locomotor hypoactivity depend on the stimulating effects that dexamethasone exert, on the protein synthesis via the glucocorticoid receptor in the brain.     

TRK-820, a selective kappa-opioid agonist, produces potent antinociception in cynomolgus monkeys

TRK-820 ((-)-17-cyclopropylmethyl-3,14b-dihydroxy-4,5a-epoxy-6b-[N-methyl-trans-3-(3-furyl)acrylamide]morphinan hydrochloride) has been shown to be a potent opioid kappa-receptor agonist with pharmacological properties different from those produced by kappa1-opioid receptor agonists in rodents. To ascertain whether or not these properties of TRK-820 would be extended to primates, the antinociceptive effect of TRK-820 was evaluated in cynomolgus monkeys by the hot-water tail-withdrawal procedure. TRK-820 given intramuscularly (i.m.) produced a potent antinociceptive effect that was 295- and 495-fold more potent than morphine with the 50 degrees C and 55 degrees C hot-water tests, respectively, and 40-fold more potent than U-50,488H and 1,000-fold more potent than pentazocine in the 50 degrees C hot-water test. The duration of antinociceptive effects of TRK-820 treatment (0.01 and 0.03 mg/kg, i.m.) lasted more than 6 h, which was much longer than those of U-50,488H. The antinociception produced by the higher dose (0.03 mg/kg, i.m.) of TRK-820 was not inhibited by nor-binaltorphimine (3.2 and 10 mg/kg, s.c.) or by naloxone (0.1 mg/kg, s.c.), although the antinociception induced by a lower dose of TRK-820 (0.01 mg/kg, i.m.) was inhibited by nor-binaltorphimine (10 mg/kg, s.c.). The same doses of nor-binaltorphimine and naloxone effectively inhibited the antinociception induced by the higher doses of U-50,488H (1.0 mg/kg, i.m.) and morphine (10 mg/kg, i.m.), respectively. These results indicate that the antinociception induced by TRK-820 is less sensitive to nor-binaltorphimine and suggest that it is mediated by the stimulation of a subtype of kappa-opioid receptor different from the kappa-opioid receptor in cynomolgus monkeys.     

Ginsenosides that produce differential antinociception in mice.

Ginsenoside Rc, Rd, and Re induced antinociception in writhing and formalin tests among five representative ginsenosides: Rb1, Rc, Rd, Re, and Rg1. However, these ginsenosides had no effect in the tail-flick test. The antinociceptive effects induced by three ginsenosides were dose dependent. ED50 was 20.5 (7.3-57.4 mg/kg) for Rc, 17 (11.0-27.6 mg/kg) for Rd, and 3.5 (1-12 mg/ kg) for Re in the writhing test and 62 (42-90 mg/kg) for Rc, 45 (20.5-99.0 mg/kg) for Rd, and 82 (48-139 mg/kg) for Re in the second phase of the formalin test. The antinociceptive effects were not blocked by the opioid receptor antagonist naloxone in the writhing and formalin tests. These three ginsenosides did not affect motor function. Ginsenoside Rc and Rd induced hypothermia for 30 to 60 min, and ginsenoside Rc induced hyperthemia after 150 min of treatment at doses of 100 mg/kg. These results suggest that ginsenosides such as Rc, Rd, or Re inhibit mainly chemogenic pain rather than thermal pain by the nonopioid system in mice.     

Antinociceptive properties of oxymorphazole in the mouse

Oxymorphazole (17-methyl-6,7-dehydro-3,14-dihydroxy-4,5 alpha-epoxy-6,7:3',4'-pyrazolomorphinan), a hydrophilic opioid, given intracerebroventricularly (2.5-50 nmol) or intrathecally (0.3-5 nmol) dose-dependently produced tail-flick inhibition in male CD-1 mice. However, oxymorphazole given subcutaneously even at high doses (10-80 mg/kg) produced weak tail-flick inhibition. Oxymorphazole given intraperitoneally (0.1 to 10 mg/kg) dose-dependently inhibited abdominal constriction response induced by intraperitoneally injection of 0.6% acetic acid. Oxymorphazole given intracerebroventricularly (25 nmol) or intrathecally (5 nmol) induced tail-flick inhibition was blocked by pretreatment with the mu-opioid receptor antagonist D-Phe-Cys-Tyr-D-Orn-Thr-Pen-Thr-NH2, but not kappa-opioid receptor antagonist nor-binaltrophimine. The delta-opioid receptor antagonist, naltrindole, blocked the tail-flick inhibition induced by oxymorphazole given intrathecally but not intracerebroventricularly. The inhibition of the abdominal constriction response by oxymorphazole given intraperitoneally was blocked by intraperitoneally pretreatment with naloxone, but not naltrindole or nor-binaltrophimine. Thus, oxymorphazole given systemically produces antinociception only with the abdominal constriction test, but not the tail-flick test, suggesting that it produces the antinociception at the peripheral sites when administered systemically. The oxymorphazole-induced antinociception is mainly mediated by the stimulation of mu-opioid receptors when given either centrally or systemically and also the delta-opioid receptors when given intrathecally. The lack of central antinociceptive effect of oxymorphazole given systemically may have interesting clinical implications.