Role of histamine in rodent antinociception.

1. Effects of substances which are able to alter brain histamine levels on the nociceptive threshold were investigated in mice and rats by means of tests inducing three different kinds of noxious stimuli: mechanical (paw pressure), chemical (abdominal constriction) and thermal (hot plate). 2. A wide range of i.c.v. doses of histamine 2HCl was studied. Relatively high dose were dose-dependently antinociceptive in all three tests: 5-100 micrograms per rat in the paw pressure test, 5-50 micrograms per mouse in the abdominal constriction test and 50-100 micrograms per mouse in the hot plate test. Conversely, very low doses were hyperalgesic: 0.5 microgram per rat in the paw pressure test and 0.1-1 microgram per mouse in the hot plate test. In the abdominal constriction test no hyperalgesic effect was observed. 3. The histamine H3 antagonist, thioperamide maleate, elicited a weak but statistically significant dose-dependent antinociceptive effect by both parenteral (10-40 mg kg-1) and i.c.v. (1.1-10 micrograms per rat and 3.4-10 micrograms per mouse) routes. 4. The histamine H3 agonist, (R)-alpha-methylhistamine dihydrogenomaleate was hyperalgesic, with a rapid effect (15 min after treatment) following i.c.v. administration of 1 microgram per rat and 3 microgram per mouse, or i.p. administration of 100 mg kg-1 in mice. In rats 20 mg kg-1, i.p. elicited hyperalgesia only 4 h after treatment. 5. Thioperamide-induced antinociception was completely prevented by pretreatment with a non-hyperalgesic i.p. dose of (R)-alpha-methylhistamine in the mouse hot plate and abdominal constriction tests. Antagonism was also observed when both substances were administered i.c.v. in rats. 6. L-Histidine HCl dose-dependently induced a slowly occurring antinociception in all three tests. The doses of 250 and 500 mg kg-1, i.p. were effective in the rat paw pressure test, and those of 500 and 1500 mg kg-1, i.p. in the mouse hot plate test. In the mouse abdominal constriction test 500 and 1000 mg kg-1, i.p. showed their maximum effect 2 h after treatment. 7. The histamine N-methyltransferase inhibitor, metoprine, elicited a long-lasting, dose-dependent antinociception in all three tests by both i.p. (10-30 mg kg-1) and i.c.v. (50-100 micrograms per rat) routes. 8. To ascertain the mechanism of action of the antinociceptive effect of L-histidine and metoprine, the two substances were also studied in combination with the histamine synthesis inhibitor (S)-alpha-fluoromethylhistidine and with (R)-alpha-methylhistamine, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Differential sensitivity of antinociceptive tests to opioid agonists and partial agonists.

1. The antinociceptive activity of a range of opioid agonists and agonist-antagonist analgesics was determined in mice by use of the 55 degrees C hot plate and abdominal constriction assays. 2. Opioid agonists were approximately 10 times more effective in the abdominal constriction assay. 3. The agonist-antagonists produced analgesia only in the abdominal constriction assay, and antagonized the antinociceptive action of opioid agonists in the 55 degrees C hot plate test. 4. These differences were shown to be attributable to the different levels of stimulus employed in the two tests. 5. By comparing the antagonist potencies of the agonist-antagonists in the 55 degrees C hot plate test with their antinociceptive ED50 values in the abdominal constriction assay, an index of intrinsic activity was calculated.     

Reversal by beta-funaltrexamine and 16-methyl cyprenorphine of the antinociceptive effects of opioid agonists in the mouse and guinea-pig

The present study compared the effects of two opioid antagonists, beta-funaltrexamine (beta-FNA) and 16-methyl cyprenorphine (RX8008M) on the antinociception produced by a range of opioid agonists in the abdominal constriction test in the mouse and the paw pressure test in the guinea-pig. Both antagonists produced large shifts in the dose-response curves to the mu-agonists, morphine and fentanyl, confirming their mu-antagonist activity. Neither antagonist produced any antagonism of the antinociceptive effects of the selective kappa-agonists U50488, U69593 and tifluadom, in the mouse. However, RX8008M produced small shifts in the dose-response curves to these agonists in the guinea-pig, which seems more likely to reflect mu-receptor activity of the agonists in the guinea-pig than lack of selectivity of the antagonists. Both beta-FNA and RX8008M produced some antagonism of bremazocine, ethyl-ketocyclazocine, proxorphan and butorphanol, indicating that these agonists have a prominent mu-receptor component to their antinociceptive actions.     

A series of novel, highly potent and selective agonists for the kappa-opioid receptor.

1. This paper describes the opioid receptor pharmacology and in vivo activity of several novel benzene-acetamidopiperidine and benzeneacetamidopiperazine analogues. 2. These compounds all showed potent, naloxone-reversible, full agonist activity in the field-stimulated rabbit vas deferens, indicating that they are kappa-opioid agonists; but showed very little activity in the rat or hamster vas deferens, indicating good selectivity with regard to mu- and delta-opioid receptors. 3. They were all potent antinociceptive agents, the most potent compound, GR 103545, having an ED50 value in the mouse abdominal constriction test of 0.25 micrograms kg-1 s.c. The compounds also produced sedation and diuresis, but had little effect on respiration rate or gastrointestinal motility. 4. It is concluded that the seven novel compounds described are all potent and selective agonists for the kappa-opioid receptor.     

The effects of systemic procaine,lidocaine and dimethocaine on nociception in mice

• 1.1. Different local anesthetics were tested for analgesic activity in three antinociceptive models, the acetic acid-induced abdominal constriction, tail-flick and hot plate tests in the mouse.
• 2.2. In the abdominal constriction test, subcutaneous, SC, injection of lidocaine (10, 20 or 30 mg/kg) and dimethocaine (5, 10 or 20 mg/kg) induced dose-dependent antinociceptive responses. Procaine (20, 30 or 50 mg/kg) was also able to reduce the response to noxious chemical stimuli.
• 3.3. The IP injection of lidocaine and dimethocaine significantly inhibited the tail-flick and paw-licking hot plate responses; procaine was weak or inactive in these tests, in which heat was the noxious stimulus
• 4.4. Taken together, these results suggest that antinociception produced by systemically administered lidocaine and dimethocaine at nontoxic doses in mice is due, at least in part, to their central effects.

     

Characterization of the antinociceptive effects of TRK-820 in the rat

We have already reported that TRK-820, (-)-17-cyclopropylmethyl-3, 14b-dihydroxy-4, 5a-epoxy-6b-[N-methyl-trans-3-(3-furyl)acrylamido]morphinan hydrochloride, a new selective kappa-opioid receptor agonist, has affinity for kappa-subtype opioid receptors other than the kappa(1)-opioid receptor. It would be of interest to examine whether the different kappa-opioid receptor subtype properties of TRK-820 participate in its antinociceptive action in the inflamed paw test and the formalin test. TRK-820 produced a potent antinociceptive effect, which was inhibited by the selective kappa-opioid receptor antagonist nor-binaltorphimine, but not by the mu-opioid receptor antagonist naloxone in the mechanical paw pressure test. TRK-820 also produced a potent antinociceptive effect in rats with adjuvant-induced arthritis. TRK-820 and morphine, a prototype mu-opioid receptor agonist, were equally effective in inhibiting the nociceptive responses in the arthritic rats and in the normal rats, while ICI-199441, 2-(3, 4-dichlorophenyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]- acetamide, a kappa-opioid receptor agonist, was about 5-fold less potent in the arthritic rats than in the normal rats. In the formalin test TRK-820 had a very similar antinociceptive potency to that of ICI-199441, unlike in the arthritic rats in which TRK-820 was 2.5 times more potent than ICI-199441. It is concluded that TRK-820 produced a potent antinociceptive action via the stimulation of kappa-opioid receptors in rats. TRK-820 has a unique antinociceptive profile different from that of the other kappa-opioid receptor agonists such as ICI-199441 in arthritic rats.     

Analgesic effects of serotonin and receptor-selective serotonin agonists in the rat spinal cord

1. Serotonin (5-HT) and selective 5-HT receptor agonists were administered intrathecally (i.t.) in rats, and the antinociceptive efficacy of these agents was assessed on the tail-flick and hot plate tests. 2. The 5-HT receptor agonists examined in this study included the 5-HT1A agonist 8-hydroxy-N,N-dipropyl-2-aminotetralin (8-OH-DPAT), the 5-HT1B agonist m-trifluoromethylphenylpiperazine (TFMPP), the 5-HT2 agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and the 5-HT3 agonist phenylbiguanide (PBG). 3. None of these agents produced significant elevations in tail-flick latency (TFL) at doses which produced elevations in hot plate latency (HPL). 4. In contrast, the i.t. dose of 5-HT which elevated TFL also produced analgesia on the hot plate test. 5. Serotonin-induced elevations in TFL were reversed by pindolol, ritanserin and ICS 205-930, suggesting that 5-HT interacts with more than one 5-HT site in the spinal cord to produce analgesia on the tail-flick test. 6. The finding that ritanserin reversed 5-HT-induced elevations in HPL suggests that the 5-HT2 site is primarily responsible for mediating the spinal antinociceptive effects of 5-HT on the hot plate test.     

Tiagabine antinociception in rodents depends on GABA(B) receptor activation: parallel antinociception testing and medial thalamus GABA microdialysis

The effects of a new antiepileptic drug, tiagabine, (R)-N-[4,4-di-(3-methylthien-2-yl)but-3-enyl] nipecotic acid hydrochloride, were studied in mice and rats in antinociceptive tests, using three kinds of noxious stimuli: mechanical (paw pressure), chemical (abdominal constriction) and thermal (hot plate). In vivo microdialysis was performed in parallel in awake, freely moving rats in order to evaluate possible alterations in extracellular gamma-aminobutyric acid (GABA) levels in a pain-modulating region, the medial thalamus. Systemic administration of tiagabine, 30 mg kg(-1) i.p., increased nearly twofold the extracellular GABA levels in rats and increased significantly the rat paw pressure nociceptive threshold in a time-correlated manner. Dose-related significant tiagabine-induced antinociception was also observed at the doses of 1 and 3 mg kg(-1) i.p. in the mouse hot plate and abdominal constriction tests. The tiagabine antinociception was completely antagonised by pretreatment with the selective GABA(B) receptor antagonist, CGP 35348, (3-aminopropyl-diethoxy-methyl-phosphinic acid) (2.5 microg/mouse or 25 microg/rat i.c.v.), but not by naloxone (1 mg kg(-1) s.c.), both administered 15 min before tiagabine. Thus, it is suggested that tiagabine causes antinociception due to raised endogenous GABA levels which in turn activate GABA(B) receptors.     

Role of the NO-cGMP pathway in the systemic antinociceptive effect of clonidine in rats and mice

The mechanism underlying the analgesic effect of clonidine, an alpha(2)-adrenoceptor agonist, remains uncertain. Activation of alpha(2)-adrenoceptor induces the release of nitric oxide (NO) from endothelial cells, which has led us to test the hypothesis that the observed antinociceptive effect induced by the systemic administration of clonidine depends on the NO-cGMP pathway. The possible involvement of an opioid link in the antinociceptive effect of clonidine was also evaluated. The antinociceptive effect induced by systemic administration (intravenous or intraperitoneal) of clonidine was evaluated using the rat paw formalin, mice tail-flick and writhing tests. Clonidine (3-120 microg/kg) induces a dose-dependent antinociceptive effect in the formalin, tail-flick and writhing tests. The antinociceptive effect of clonidine in a dose that had no sedative effect assessed by rota rod test, was significantly reduced by NO-synthase and guanylyl cyclase inhibition. The antinociceptive effect of morphine, but not clonidine, was inhibited by naloxone. Our current results suggest that the antinociceptive effect of systemic clonidine does not involve the opioid receptor and is modulated by the NO-cGMP pathway.     

Evaluation of analgesic and anti-inflammatory activities of Nectandra megapotamica (Lauraceae) in mice and rats

The bioactivity-guided phytochemical investigation of the crude hydralcoholic extract of Nectandra megapotamica was carried out using the abdominal constriction test in mice, which led to the isolation of three active compounds: alpha-asarone (1), galgravin (2) and veraguensin (3). The crude extract (EBCA, 300 mg kg(-1)) and isolated compounds 1,2, and 3, at different doses, were evaluated using the acetic acid-induced abdominal constriction test in mice, carrageenan-induced paw oedema in rats, and hot plate tests in rats. The EBCA showed a significant effect in the abdominal constriction and hot plate tests, but did not show activity in the rat paw oedema assay. All isolated compounds displayed activity in the abdominal constriction test, but only compound 1 was active in the hot plate test. Compounds 2 and 3 displayed activity in the anti-inflammatory assay. It was suggested that the analgesic effects obtained for EBCA could be due mainly to the presence of its major compound, alpha-asarone (1).     

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.     

HS-599: a novel long acting opioid analgesic does not induce place-preference in rats

1. When administered subcutaneously HS-599, a new didehydroderivative of buprenorphine (18,19-dehydrobuprenorphine), produced a long-lasting antinociceptive response in rats. Its potency exceeded twice that of buprenorphine. In the tail-flick test it acted as a full agonist but in the plantar test only as a partial agonist. Whereas the mu-opioid antagonists naloxone and naltrexone antagonized HS-599 antinociception the delta-opioid antagonist naltrindole and the kappa-opioid antagonist nor-binaltorphimine did not. 2. Unlike buprenorphine and morphine, HS-599 never induced conditioned place-preference in rats. 3. In radioligand binding assays, compared with buprenorphine HS-599 had 3 fold higher mu-opioid receptor affinity but lower delta- and kappa-opioid receptor affinity. 4. In isolated guinea-pig ileum preparations, HS-599 only partially inhibited the electrically-stimulated contraction, acting as a partial opioid agonist. When tested against the mu-opioid receptor agonist dermorphin, it behaved as a non-equilibrium antagonist. Conversely, in mouse vas deferens (rich in delta-opioid receptors) and rabbit vas deferens preparations (rich in kappa-opioid receptors) HS-599 acted as a pure equilibrium antagonist, shifting the log-concentration-response curves of the delta-opioid agonist deltorphin I and the kappa-opioid agonist U-69593 to the right. 5. In conclusion, HS-599 is a novel buprenorphine derivative with higher affinity, selectivity and potency than the parent compound, for mu-opioid receptors. It produces intense and long-lasting antinociception and does not induce place-preference in rats.     

A study of the interaction between clonidine and morphine on analgesia and blood pressure during continuous intrathecal infusion in the rat

In the rat, the continuous intrathecal (i.t.) infusion of clonidine (0.4 microgram/hr) significantly increased the tail-flick latency (TF) and the threshold for paw pressure (PP) withdrawal for 5 days and decreased the systolic blood pressure (up to 24 mm Hg) for 7 days. The antinociceptive effect of continuous intrathecal infusion of clonidine (0.4 microgram/hr) in the tail flick and paw pressure tests was not attenuated in rats that were tolerant to morphine. The acute intrathecal administration of clonidine (2.7 micrograms) and morphine (1.0 microgram) resulted in a synergistic interaction in the tail-flick and paw pressure tests. A synergistic interaction was also observed during the continuous intrathecal infusion of morphine (1.25 micrograms/hr) and clonidine (0.2 microgram/hr) in the tail-flick and paw pressure tests. Individually, these doses of morphine and clonidine had no antinociceptive effect. However, intrathecal infusion together yielded peak tail-flick and paw pressure responses comparable to that of 0.4 microgram/hr clonidine alone, without affecting systolic blood pressure. No delay in the onset of tolerance to the analgesic effect was observed with the combination as compared with clonidine (0.4 microgram/hr) alone. The data indicate that clonidine-induced spinal analgesia is independent of endogenous opioid systems linked to mu-receptors in the spinal cord, and that optimization of spinal analgesia (e.g. synergism) can be achieved during continuous intrathecal infusion without affecting cardiovascular activity.     

Evidence that the kappa agonist U50488H has non-opioid actions

The antagonism of the antinociceptive effects of various kappa-opioid agonists has been studied in the mouse abdominal constriction test. Naloxone produced a much smaller degree of antagonism of U50488H than it did of two other kappa-agonists, U69593 and tifluadom. The kappa-selective antagonist, norbinaltorphimine, also failed to shift the dose-response curve to U50488H in this test, despite producing considerable antagonism of the U50488H effect in the rotarod test and of U69593 in both experimental situations. These results are suggestive of a non-opioid component to the action of U50488H in the abdominal constriction test. At high concentrations, U50488H, but not U69593, also showed non-opioid effects in reducing contractile activity in the field-stimulated isolated guinea-pig ileum, as demonstrated by the profile of antagonism seen with beta-chlornaltrexamine and naloxone. These results suggest that U69593, rather than U50488H, may be the kappa-agonist of choice to use, particularly in in-vivo experiments.     

Study of the involvement of K+ channels in the peripheral antinociception of the kappa-opioid receptor agonist bremazocine

The involvement of the nitric oxide (NO)/cyclic GMP pathway in the molecular mechanisms of antinociceptive drugs like morphine has been previously shown by our group. Additionally, it is known that the desensitisation of nociceptors by K(+) channel opening should be the final target for several analgesic drugs including nitric oxide donors and exogenous micro-opioid receptor agonists. In our previous study, we demonstrated that bremazocine, a kappa-opioid receptor agonist, induces peripheral antinociception by activating nitric oxide/cyclic GMP pathway. In the current study, we assessed whether bremazocine is capable to activate K(+) channels eliciting antinociception. Bremazocine (20, 40 and 50 microg) dose-dependently reversed the hyperalgesia induced in the rat paw by local injection of carrageenan (250 microg) or prostaglandin E(2) (2 microg), measured by the paw pressure test. Using the selective kappa-opioid receptor antagonist nor-binaltorphimine (Nor-BNI, 200 microg/paw), it was confirmed that bremazocine (50 microg/paw) acts specifically on the kappa-opioid receptors present at peripheral sites. Prior treatment with the ATP-sensitive K(+) channel blockers glibenclamide (40, 80 and 160 microg) and tolbutamide (40, 80 and 160 microg) did not antagonise the antinociceptive effect of bremazocine (50 microg). The same results were obtained when we used prostaglandin E(2) (2 microg) as the hyperalgesic stimulus. The supposed participation of other types of K(+) channels was tested using the Ca(2+)-activated K(+) channel blockers dequalinium (12.5, 25 and 50 microg) and charybdotoxin (0.5, 1 and 2 microg) and different types of the non-selective K(+) channel blockers tetraethylammonium (25, 50 and 100 microg) and 4-aminopyridine (10, 25 and 50 microg). None of the K(+) channel blockers reversed the antinociceptive effect of bremazocine. On the basis of these results, we suggest that K(+) channels are not involved in the peripheral antinociceptive effect of bremazocine, although this opioid receptor agonist induces nitric oxide/cGMP pathway activation.     

Studies on o-methylflavinantine

The antinociceptive effects of O-methylflavinantine (OMF), a morphinandienone alkaloid, were investigated in the mouse hot plate and abdominal constriction tests (nociceptive agents: 5-Hydroxytryptamine, acetylcholine, bradykinin, prostaglandin, E (1) (PGE (1), formic acid and phenylquinone). The potency of OMF in the hot plate test was approximately 10 times less than that of morphine and the effect was naloxone reversible. In the abdominal constriction test, morphine was 78-650 times more potent than OMF, depending on the nociceptive agent used, but a higher dose of naloxone was necessary to reverse the response to formic acid. Pretreatment of mice with reserpine (1 mg/kg, s.c., 24 h) reduced and alpha-methyl-p-tyrosine (200 mg/kg, i.p., 3 h) potentiated the antinociceptive effects of both morphine and OMF in the hot plate test. The results are considered to indicate that OMF possesses centrally mediated antinociceptive activity which is similar to that of morphine.     

Modification of kappa-opioid receptor agonist-induced antinociception by diabetes in the mouse brain and spinal cord

The supraspinal and spinal antinociceptive effects of several kappa-opioid receptor agonists were examined in diabetic and non-diabetic mice using the tail-flick assay. The antinociception induced by intrathecal (i.t.), but not intracerebroventricular (i.c.v.), CI-977, a highly selective kappa(1)-opioid receptor agonist, in diabetic mice was less than that in non-diabetic mice. The antinociceptive effects of ICI-199,441 and R-84760, high potency kappa(1)-opioid receptor agonists, given i.c.v., but not i.t., were attenuated in diabetic mice compared to those in non-diabetic mice. On the other hand, the antinociceptive effects of the new kappa-opioid receptor agonist TRK-820, which has high affinity for kappa(2)- and/or kappa(3)-opioid receptors, injected both i.c.v. and i.t. in diabetic mice were markedly less than those in non-diabetic mice. These results indicate that the antinociceptive effects of those kappa-opioid receptor agonists in diabetic mice are altered in a region-specific manner in the central nervous system (CNS). The dysfunction of kappa-opioid receptor subtypes in diabetic mice may underlie this CNS region-specific variation in the effects of these kappa-opioid receptor agonists.     

Facilitation of enkephalins catabolism inhibitor-induced antinociception by drugs classically used in pain management.

The aim of this study was to investigate the facilitatory effects of subanalgesic or low doses of different drugs (acetylsalicylic acid, ibuprofen and morphine) on the antinociceptive responses induced by the endogenous opioid peptides, enkephalins, protected from their catabolism by the dual enkephalin-degrading enzymes inhibitor RB101. According to the analgesic profile of the three studied compounds different antinociceptive assays were used: the hot plate and formalin tests in mice, and the tail flick and paw pressure tests on inflamed paws in rats and polyarthritic rats. Facilitatory effects of subanalgesic doses of acetylsalicylic acid and ibuprofen on RB101-induced antinociceptive responses were observed in the early and late phases of the formalin test, respectively. In the hot plate, tail flick and paw pressure tests, the dose-dependent analgesic effects of RB101 were strongly potentiated by subanalgesic doses of morphine (0.5 mg/kg), while in these tests, acetylsalicylic acid and ibuprofen were unable to modify the RB101-induced antinociceptive responses. The synergism in antinociceptive effects observed with the combination of RB101 and morphine supported by isobolographic analysis, may have interesting clinical implications, considering both the lack of opiate drawbacks observed with RB101 and the high potentiation of its antinociceptive effects with very low doses of morphine.     

MGM-9 [(E)-methyl 2-(3-ethyl-7a,12a-(epoxyethanoxy)-9-fluoro-1,2,3,4,6,7,12,12b-octahydro-8-methoxyindolo[2,3-a]quinolizin-2-yl)-3-methoxyacrylate], a derivative of the indole alkaloid mitragynine: a novel dual-acting mu- and kappa-opioid agonist with potent antinociceptive and weak rewarding effects in mice

Mitragynine is a major indole alkaloid isolated from the Thai medicinal plant Mitragyna speciosa that has opium-like properties, although its chemical structure is quite different from that of morphine. We attempted to develop novel analgesics derived from mitragynine, and thus synthesized the ethylene glycol-bridged and C10-fluorinated derivative of mitragynine, MGM-9 [(E)-methyl 2-(3-ethyl-7a,12a-(epoxyethanoxy)-9-fluoro-1,2,3,4,6,7,12,12b-octahydro-8-methoxyindolo[2,3-a]quinolizin-2-yl)-3-methoxyacrylate]. We hypothesized that a dual-acting mu- and kappa-opioid agonist could produce potent antinociceptive effects with fewer rewarding effects compared with mu agonists. In this study, MGM-9 exhibited high affinity for mu- and kappa-opioid receptors with Ki values of 7.3 and 18 nM, respectively. MGM-9 showed a potent opioid agonistic effect, and its effects were meditated by mu- and kappa-opioid receptor mechanisms in in vitro assays. Subcutaneous and oral administration of MGM-9 produced potent antinociceptive effects in mouse tail-flick, hot-plate, and writhing tests. When administered orally, the antinociceptive effect of MGM-9 was seven to 22 times more potent than that of morphine. The antinociceptive effects of MGM-9 were mediated by both mu- and kappa-opioid receptors. Subcutaneous administration of MGM-9 twice daily for 5 days led to antinociceptive tolerance. In the gastrointestinal transit study, MGM-9 inhibited gastrointestinal transit, but its effect was weaker than that of morphine at equi-antinociceptive doses. Furthermore, MGM-9 induced less hyperlocomotion and fewer rewarding effects than morphine. The rewarding effect of MGM-9 was blocked by a mu antagonist and enhanced by a kappa antagonist. Taken together, the results suggest that MGM-9 is a promising novel analgesic that has a stronger antinociceptive effect and weaker adverse effects than morphine.     

Antagonism of U-50,488H-induced antinociception by ginseng total saponins is dependent on serotonergic mechanisms.

Morphine-induced antinociception was prevented by pretreatment with ginseng total saponins in the tail-pinch and tail-flick tests carried out in mice. The antinociceptive effect of U-50,488H, a selective kappa-opioid receptor agonist, was prevented by naloxone, a nonselective opioid receptor antagonist, in the tail-pinch but not in the tail-flick test. However, U-50,488H-induced antinociception was prevented by ginseng total saponins in the tail-flick but not in the tail-pinch test. These results indicate that nonopioid mechanisms are involved in the antagonism of U-50,488H-induced antinociception by ginseng total saponins. In addition, the antagonism of U-50,488H-induced antinociception in mice pretreated with ginseng total saponins was abolished by pretreatment with a serotonin precursor, 5-hydroxytryptophan, but not by a noradrenaline precursor, L-dihydroxyphenylalanine, in the tail-flick test. Therefore, it appears that the antagonism of U-50,488H-induced antinociception by ginseng total saponins is dependent on serotonergic mechanisms.