Glutamate-induced Nociception Research Articles

Antinociceptive Effect of the Essential Oil Obtained from the Leaves of Croton cordiifolius Baill. (Euphorbiaceae) in Mice.

Croton cordiifolius Baill. is a shrub known as “quebra-faca” and is used to treat inflammation, pain, wounds, and gastrointestinal disturbances in the semiarid region in the northeast of Brazil. In an ethnobotanical survey in the state of Pernambuco, “quebra-faca” use was cited in 33% of the interviews. Thus, we decided to evaluate the antinociceptive effects of the essential oil from C. cordiifolius (CcEO). Chemical analysis by gas chromatography-mass spectrometry revealed 1,8-cineole (25.09%) and α-phellandrene (15.43%) as major constituents. Antinociceptive activity was evaluated using murine models of chemically induced pain (writhing induced by acetic acid, formalin, capsaicin, and glutamate tests). Opioid and central nervous systems (CNS) involvement were also investigated. Regarding antinociceptive activity, CcEO (50 and 100 mg/kg) reduced the number of writhing responses induced by acetic acid and decreased the licking times in both phases of the formalin test. CcEO also was evaluated in capsaicin- and glutamate-induced nociception. While no effect was observed in the capsaicin test, CcEO (100 mg/kg) was effective in the glutamate test. Naloxone, an opioid antagonist, did not affect the antinociceptive activity of CcEO in writhing test. In conclusion, the antinociceptive effect of CcEO could be explained, at least in part, by inhibition of the glutamatergic system.

Antinociceptive and anti-hyperalgesic effects of bis(4-methylbenzoyl) diselenide in mice: Evidence for the mechanism of action

Context: The organoselenium compounds have been described to demonstrate several biological activities, including pain management.Objective: This study investigated the antinociceptive, hyperalgesic, and toxic effects of oral administration of bis(4-methylbenzoyl) diselenide (BMD) in mice.Materials and methods: The antinociceptive and anti-hyperalgesic effects of BMD (1, 5, 10, 25, and 50 mg/kg, p.o.) were evaluated using models of nociception: formalin, capsaicin, bradykinin (BK), cinnamaldehyde, phorbol myristate acetate (PMA), 8-bromo-cAM, and glutamate-induced nociception; and mechanical hyperalgesia induced by carrageenan (Cg) or complete Freund's adjuvant (CFA). The acute toxicity was evaluated by biochemical markers for hepatic and renal damages.Results: BMD significantly inhibited the licking time of the injected paw in the early and late phases of a formalin test with ED50 values of 14.2 and 10.8 mg/kg, respectively. This compound reduced nociception produced by capsaicin (ED50 of 32.5 mg/kg), BK (ED50 of 24.6 mg/kg), glutamate (ED50 of 28.7 mg/kg), cinnamaldehyde (ED50 of 18.9 mg/kg), PMA (ED50 of 9.6 mg/kg), and 8-bromo-cAMP (ED50 of 24.8 mg/kg). In the glutamate test, the pretreatment with nitric oxide (NO) precursor, l-arginine, reversed antinociception caused by BMD or Nω-nitro-l-arginine (L-NOARG), but the effect of BMD was not abolished by naloxone. Mechanical hyperalgesia induced by Cg and CFA was attenuated by BMD, 70 ± 4% and 65 ± 4%, respectively. Furthermore, a single oral dose of BMD did not change plasma aspartate (AST) and alanine aminotransferase (ALT) activities or urea and creatinine levels.Conclusion: BMD demonstrated as a promising compound because of the antinociceptive and anti-hyperalgesic properties in mice.

Serotonergic systems are implicated in antinociceptive effect of m-trifluoromethyl diphenyl diselenide in the mouse glutamate test

The organoselenium compound m-trifluoromethyl diphenyl diselenide (m-CF3-PhSe)2 has antinociceptive actions in several animal models, which are mediated by interaction with endogenous opioid systems. It also shows antidepressant-like action mediated by both opioid and serotonergic systems. Considering that serotonin (5-HT) plays an important role in the descending control of pain, this study further investigated the role of serotonergic systems in the antinociceptive action of (m-CF3-PhSe)2 in the glutamate-induced licking behavior model in mice. (m-CF3-PhSe)2 (1–50mg/kg, p.o.), morphine (2.5mg/kg, s.c.) or paroxetine (5mg/kg, i.p.) reduced glutamate-induced nociception. Selective 5-HT1A and 5-HT2A receptor antagonists, WAY100635 (0.7mg/kg, i.p.) and ketanserin (0.3mg/kg, i.p.), but not the selective 5-HT3 receptor antagonist, ondansetron (0.5mg/kg, i.p.), prevented the antinociceptive effect of (m-CF3-PhSe)2 (10mg/kg) in the glutamate test. In biochemical studies, (m-CF3-PhSe)2 (10 and 50mg/kg) decreased [3H]5-HT uptake in crude synaptosomes of mouse brains and slightly inhibited in vitro [3H]5-HT binding. In kinetic studies, the selenium (Se) distribution was determined at different time points after the administration of (m-CF3-PhSe)2 (500mg/kg, p.o.) to mice. After 30min, a high amount of Se was found in liver and kidneys, followed by the lung, red blood cells, serum and brain. A significant amount of Se accumulated in fat over the course of 8h. Urine was an important route of Se excretion originating from (m-CF3-PhSe)2. Collectively, results of this study indicate an involvement of the serotonergic systems in the antinociceptive effect of (m-CF3-PhSe)2 and a wide distribution of Se derived from this compound.

Antinociceptive activity of Syzygium cumini leaves ethanol extract on orofacial nociception protocols in rodents

Context: Syzygium cumini (L.) Skeels (Myrtaceae) is a tree with dark purple fruits, popularly known as “jambolão” or “jambolan”. In folk medicine, this plant is used for the treatment of diabetes and inflammatory conditions.Objective: We investigated the antinociceptive effect of ethanol extract (EE) from S. cumini leaves on orofacial nociception.Material and methods: The antinociceptive effects of the EE obtained from the leaves of S. cumini were evaluated in mice using formalin- and glutamate-induced orofacial nociception.Results: ESI-MS/MS analyses demonstrated that major constituents in the analyzed samples coincided with the mass of the phenolic acids and flavonoids. In pharmacological approach, pre-treatment with EE (100, 200, or 400 mg/kg, p.o.) significantly reduced (p < 0.05 or p < 0.01) the percentage of paw licks time during phase 2 (43.2, 47.1, and 57.4%, respectively) of a formalin pain test when compared to control group animals. This effect was prevented by pretreatment with glibenclamide and NG-nitro-l-arginine (l-NOARG). The extract, all doses, also caused a marked inhibition (p < 0.01 or p < 0.001) of glutamate-induced orofacial nociception (38.8, 51.7, and 54.7%) when compared with the control group. No effect was observed with the rota-rod model.Conclusions: We can suggest that the antinociceptive effect of the EE is mediated by peripheral mechanisms, possibly involving KATP channels and the nitric oxide pathways. These effects appear to be related to the presence of flavonoids compounds, such as quercetin.

Cyclodextrin‐complexed Lippia grata essential oil reduce c‐fos expression in the periaqueductal gray area following the antinociceptive effect in mice

Lippia grata Schauer (Verbenaceae) leaves essential oil/β‐cyclodextrin (EO/β‐CD) complex was used to evaluated if the complex formulation is able in reduces orofacial behavior in mice. Male Swiss mice were pretreated with EO/β‐CD (50, 100 and 200 mg/kg, p.o., per os, orally), morphine (5 mg/kg, i.p.) or vehicle (distilled water). Ninety minutes after the treatment, we injected formalin (20 μL, 2%), capsaicin (20 μL, 2.5 μg) or glutamate (40μL, 25 μM) into the right upper lip (perinasal area). For the action in the CNS, 90 minutes after the treatment, the animals were perfused, the brains collected, and submitted in an immunofluorescence protocol for Fos protein. Experimental protocols were approved by the Animal Care and Use Committee at the UFS (# 57/11). EO/β‐CD produced significant (p&lt; 0,05; p&lt;0.01) antinociceptive effect, in the formalin‐, capsaicin‐and glutamate‐induced orofacial nociception. The immunofluorescence showed that the EO/β‐CD activated significantly (p&lt;0.05) the olfactory bulb, the piriform cortex, and the periaqueductal grey of the CNS. Together, our results provide first‐time evidence that EO/β‐CD attenuates orofacial nociception at least, in part, through an activation of CNS areas, such as periaqueductal grey.

Antinociceptive effect of 7-methoxyflavone isolated from Zornia brasiliensis

In this study, we investigated the antinociceptive effect of 7-methoxyflavone (7MF) in mice using the following tests: acetic acid-induced writhing, glutamate- and formalin-induced nociception and hotplate. 7MF (30, 50, 100 and 300 μmol/kg, i.p.) reduced the number of writhes, with ID50 = 82.5 ± 11.7 μmol/kg and E max = 58.4%. 7MF treatment (100 μmol/kg, i.p.) inhibited paw-licking time in the neurogenic phase of the formalin pain response (65.6%) and did not decrease the nociceptive response in the inflammatory phase. In addition, in glutamate-induced nociception, 7MF inhibited 26% of the nociceptive answer. On the other hand, 7MF did not increase the latency time of the animals in the hotplate test. These results suggest that 7MF has peripheral antinociceptive activity.

Kavain analogues as potential analgesic agents

BackgroundKavalactones are pharmacologically active compounds present in preparations of the root trunk of Piper methysticum Forst, known as kava. This work describes the analgesic activity of some synthesized analogues of synthetic kavain, which is the main component of kava. MethodsThe essays were initially performed against the writhing test in mice, and the most promising compound was analyzed using other classical models of nociception, including formalin-, capsaicin-, glutamate-induced nociception, the hot plate test, and measurement of motor performance. ResultsThe results indicated that compound 6-(4-fluorophenyl)-4-methoxy-5,6-dihydropyran-2-one (2d) exerts potent and dose-dependent analgesic activity, inhibiting abdominal constrictions caused by acetic acid in mice, and being more active than some reference drugs. It also presented activity in the other models of pain, with the exception of the hot plate test and the measurement of motor performance. ConclusionsAlthough compound 2d exerts antinociceptive activity, the mechanism of action remains uncertain, but it does not involve the opioid system and does not appear to be associated with non-specific effects such as changes in locomotor activity or motor coordination.

Orofacial Analgesic-Like Activity of Carvacrol in Rodents

Carvacrol (CARV) is a phenolic monoterpene present in the essential oil of several aromatic spices. The purpose of the present study was to evaluate the antinociceptive effect of CARV on formalin-, capsaicin-, and glutamate-induced orofacial nociception in mice. Male mice were pretreated with CARV [25, 50, and 100 mg/kg body weight (BW), intraperitoneal (i.p.)], morphine (5 mg/kg BW, i.p.), or vehicle (distilled water + one drop of 0.3% cremophor in distilled water), before formalin (20 microl, 2%), capsaicin (20 microl, 2.5 microg), or glutamate (40 microl, 25 microM) was injected into the right upper lip. Our results revealed that i.p. pretreatment with CARV was effective in reducing the nociceptive face-rubbing behaviour in both phases of the formalin test and also produced a significant antinociceptive effect at all doses in the capsaicin and glutamate tests. Further, we showed that the action of CARV on the central nervous system (CNS) did not affect these results, since this compound did not exert a significant CNS-depressant effect, as shown by the pentobarbital-induced hypnosis. Our results suggest that CARV might represent an important tool for the treatment of orofacial pain.

Antinociceptive and anti-inflammatory activities of crude methanolic extract of red alga Bryothamnion triquetrum.

The marine environment is an extraordinary reservoir of bioactive natural products, many of which exhibit chemical and structural features not found in terrestrial natural products. In this regard, the aim of this study was to investigate the possible antinociceptive and anti-inflammatory activities of a crude methanolic extract of the red alga Bryothamnion triquetrum (BT-MeOH) in murine models. Groups of Swiss mice of both sexes (25–30 g) were used throughout the experiments. The potential antinociceptive of BT-MeOH was evaluated by means of the following tests: acetic acid-induced writhing, hot-plate test and glutamate- and formalin-induced nociception. The anti-inflammatory activity of BT-MeOH was investigated using the zymosan A-induced peritonitis test. The tests were conducted using 100 mg/kg (p.o.) BT-MeOH, 33.3 mg/kg (p.o.) dipyrone, 35.7 mg/kg (p.o.) indomethacin and 5.7 mg/kg (s.c.) morphine. The extract and all standard drugs were administered 40 min before the nociceptive/inflammatory stimulus. In the acetic acid-induced writhing test, BT-MeOH and dipyrone inhibited the nociceptive response by 55.9% (22.2 ± 2.0 writhings; p < 0.01) and 80.9% (9.6 ± 2.1 writhings; p < 0.01). In the hot-plate test, BT-MeOH did not increase the latency time of the animals in the time evaluated. In addition, BT-MeOH inhibited glutamate-induced nociception by 50.1%. While BT-MeOH did not inhibit the neurogenic phase in formalin-induced nociception, the inflammatory phase was inhibited by 53.1% (66.8 ± 14.2 s; p < 0.01). Indomethacin inhibited the inflammatory phase by 60.2% (56.8 ± 8.7 s; p < 0.01). In the zymosan-induced peritonitis test, BT-MeOH inhibited 55.6% (6.6 ± 0.2 × 106 leukocytes/mL; p < 0.01) of leukocyte migration, while indomethacin inhibited 78.1% (3.2 ± 0.1 × 106 leukocytes/mL; p < 0.01). Based on the results obtained in this study, we conclude that BT-MeOH has peripheral antinociceptive and anti-inflammatory activities. However, more studies need to be conducted to confirm these properties.

Evaluation of antinociceptive effects of Crassocephalum bauchiense Hutch (Asteraceae) leaf extract in rodents

Ethnopharmacological relevanceThe leaves of Crassocephalum bauchiense have long been used in traditional Cameroonian medicine for the treatment of epilepsy, pain, inflammatory disorders, arthritis and intestinal pain. Aim of the studyIn this study, we attempted to identify the possible antinociceptive action of the aqueous extract and the alkaloid fraction prepared from the leaves of Crassocephalum baucheiense. Materials and methodsUsing acetic acid induced abdominal constrictions, formalin-, capsaisin- and glutamate-induced nociception, and hot plate assay procedures, the antinociceptive effects of the aqueous extract and the alkaloid fraction was assessed after oral administration in mice. Morphine sulfate was used as reference analgesic agent. Mice were submitted to the rota-rod task and open-field test in order to assess any non-specific muscle-relaxant or sedative effects of the extracts of Crassocephalum bauchiense. Male and female Swiss mice were used to assess acute toxicity of these extracts. ResultsThe aqueous extract and the alkaloid fraction of Crassocephalum bauchiense produced a significant antinociceptive effects in the acetic acid, formalin, glutamate, capsaicin and hot plate tests. These antinociceptive effects of Crassocephalum bauchiense were significantly attenuated by pretreatment with naloxone. The extracts of Crassocephalum bauchiense did not alter the locomotion of animals in the open-field or rotarod tests, which suggest a lack of a central depressant effect. The animals did not exhibit any acute toxicity to the aqueous extract and the alkaloid fraction, so it was not possible to calculate the LD50. ConclusionThe results confirm the popular use of Crassocephalum bauchiense as an antinociceptive, and contribute to the pharmacological knowledge of this species because it was shown that the aqueous extract and the alkaloid fraction of Crassocephalum bauchiense produced dose related antinociception in models of chemical and thermal nociception through mechanisms that involve an interaction with opioidergic pathway.

Sida cordifolia Leaf Extract Reduces the Orofacial Nociceptive Response in Mice

In this study, we describe the antinociceptive activity of the ethanol extract (EE), chloroform (CF) and methanol (MF) fractions obtained from Sida cordifolia, popularly known in Brazil as "malva branca" or "malva branca sedosa". Leaves of S. cordifolia were used to produce the crude ethanol extract and after CF and MF. Experiments were conducted on Swiss mice using the glutamate and formalin-induced orofacial nociception. In the formalin test, all doses of EE, CF and MF significantly reduced the orofacial nociception in the first (p < 0.001) and second phase (p < 0.001), which was also naloxone-sensitive. In the glutamate-induced nociception test, only CF and MF significantly reduced the orofacial nociceptive behavior with inhibition percentage values of 48.1% (100 mg/kg, CF), 56.1% (200 mg/kg, CF), 66.4% (400 mg/kg, CF), 48.2 (200 mg/kg, MF) and 60.1 (400 mg/kg, MF). Furthermore, treatment of the animals with EE, CF and MF was not able to promote motor activity changes. These data demonstrate that S. cordifolia has a pronounced antinociceptive activity on orofacial nociception. However, pharmacological and chemical studies are necessary in order to characterize the responsible mechanisms for this antinociceptive action and also to identify other bioactive compounds present in S. cordifolia.

Antinociceptive activity of carvacrol in formalin-, capsaicin- and glutamate-induced orofacial nociception in rodents

Antinociceptive activity of carvacrol in formalin-, capsaicin- and glutamate-induced orofacial nociception in rodents

Further analyses of mechanisms underlying the antinociceptive effect of the triterpene 3β, 6β, 16β-trihydroxylup-20(29)-ene in mice

The present study investigated the mechanisms involved in the antinociception produced by the triterpene 3β, 6β, 16β-trihydroxylup-20(29)-ene (TTHL) in mice. TTHL administered by intra-gastric (i.g.) gavage inhibited glutamate-induced nociception with an ID50 of 19.0 (13.2–27.5) mg/kg. This action started 60min (inhibition of: 59±6%) after i.g. administration and remained significant up to 6h (inhibition of 37±6%). Moreover, TTHL inhibited both phases of formalin induced pain. The antinociception of TTHL was reversed by the pre-administration of naloxone (1mg/kg; non-selective opioid receptor antagonist), CTOP (1mg/kg; selective μ-opioid receptor antagonist), nor-binaltorphimine (1mg/kg; selective κ-opioid receptor antagonist), naltrindol (3mg/kg; selective δ-opioid receptor antagonist), p-chlorophenylalanine methyl ester (100mg/kg for 4 consecutive days; inhibitor of serotonin synthesis), WAY100635 (0.5mg/kg; selective 5-HT1A receptor antagonist) and ketanserin (0.3mg/kg; selective 5-HT2A receptor antagonist) but not by L-arginine (600mg/kg; nitric oxide precursor) or ondansetron (0.5mg/kg; 5-HT3 receptor antagonist). Furthermore, the TTHL antinociception was prevented by intrathecal (i.t.) pre-treatment with pertussis toxin (0.5μg/site; inactivator of Gi/o protein), charybdotoxin (250pg/site; blocker of large-conductance calcium-gated K+ channels), tetraethylammonium (1μg/site; blocker of voltage-gated K+ channels) and glibenclamide (80μg/site; blocker of ATP-gated K+ channels) but not by apamin (50ng/site; blocker of small-conductance calcium-gated K+ channels). The antinociception of TTHL was not it associated with locomotor impairment or sedation. These results showed that TTHL presented a pronounced antinociceptive effect, which is dependent on opioid and serotonergic systems, Gi/o protein activation and the opening of specific K+ channels.

Antinociceptive properties of conocarpan and orientin obtained from Piper solmsianum C. DC. var. solmsianum (Piperaceae)

The antinociceptive properties of some fractions and two pure compounds, conocarpan and orientin, obtained from P. solmsianum leaves were investigated in several models of pain in mice. The results indicated that this plant exhibits a promising antinociceptive profile, as it produces active principles which are several times more active than some reference drugs used for comparison. The main compound tested, orientin, caused potent and dose-dependent effects against acetic acid-induced writhing and capsaicin- and glutamate-induced nociception, being more effective against the first one, with an ID(50) value of 6.5 mg/kg (14.5 micromol/kg). Orientin was about 20-fold more potent than acetylsalicylic acid and 3.5-fold more active than indomethacin. The antinociceptive effects of this plant may be attributed, at least partially, to the presence of conocarpan and, in particular, to the flavonoid orientin.

Spinal antinociception evoked by the triterpene 3β, 6β, 16β-trihydroxylup-20(29)-ene in mice: Evidence for the involvement of the glutamatergic system via NMDA and metabotropic glutamate receptors

The present study investigated the possible involvement of the glutamatergic and neurokinin systems in the antinociception caused by triterpene 3β, 6β, 16β-trihydroxylup-20(29)-ene (TTHL) in mice. TTHL given by intraperitoneal (i.p., 2.1–65.5 µmol/kg), intraplantar (i.pl., 6.5–65.5 nmol/paw) or intrathecal (i.t., 21.8–655 nmol/site) routes, produced dose-dependent inhibition of glutamate-induced nociception with ID 50 values of 12 µmol/kg; 34.2 nmol/paw; 233.8 nmol/site and inhibitions of 78 ± 6; 82 ± 4 and 77 ± 8%, respectively. I.t. injection of TTHL (6.5–218 nmol/site, co-administered) also caused significant and dose-dependent reduction of nociceptive response induced by i.t. injection of glutamate (175 nmol/site), with ID 50 value of 54.5 nmol/site and inhibition of 51 ± 6%. Moreover, TTHL (65.5 nmol/site) co-injected by i.t. route with agonist caused marked reduction of nociceptive responses induced by N-methyl- d-aspartate (NMDA, 450 pmol/site), (±)-1-aminocyclopentane-trans-1,3 dicarboxylic acid (trans-ACPD, 10 nmol/site) and substance P (100 pmol/site), with inhibitions of 81 ± 7; 79 ± 7; 81 ± 11%, respectively. Conversely, TTHL had no effect on α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA, 135 pmol/site) and kainic acid (kainate, 110 pmol/site)-induced nociception. Moreover, the association of sub-effective doses of TTHL (6.5 nmol/site, i.t.) and MK-801(1 nmol/site, i.t.; non-competitive NMDA antagonist) or (RS)-MCPG (30 nmol/site, i.t.; non-selective group I/group II metabotropic glutamate receptor antagonist) produced a synergic antinociceptive effect in the nociception induced by NMDA or trans-ACPD, respectively. Together, these results provide experimental evidence for the involvement of the glutamatergic system (NMDA and metabotropic glutamate receptors) in the antinociceptive action caused by TTHL in mice.

Analgesic activity of 3-mono-substituted derivatives of dihydrofuran-2-one in experimental rodent models of pain

Three derivatives of dihydrofuran-2-one (L-PP, L-PP1, and L-SAL) were administered by intraperitoneal injection and their analgesic activity was assayed in several models of pain. The activity of these derivatives were tested using a hot plate test, a writhing test, capsaicin- and glutamate-induced nociception, along with two models of local anesthesia, including a test for infiltration anesthesia in guinea pigs and the modified tail immersion test in mice. The results of these in vivo experiments show that these three derivatives of dihydrofuran-2-one possess analgesic activity in rodents. The ED50 values of the tested compounds are lower or comparable to the ED50 values of reference compounds (acetylsalicylic acid or morphine). For the most active derivative of dihydrofuran-2-one, L-PP1 (3-[4-(3-trifluoromethylphenyl)-piperazin-1-yl]-dihydrofuran-2-one dihydrochloride), the ED50 value was: 1.34mg/kg, 0.79mg/kg, 2.01mg/kg and 3.99mg/kg in the hot plate, writhing, capsaicin- and glutamate-induced pain tests, respectively.

Evidence for the involvement of ionotropic glutamatergic receptors on the antinociceptive effect of (−)-linalool in mice

(-)-Linalool is a monoterpene alcohol which is present in the essential oils of several aromatic plants. Recent studies suggest that (-)-linalool has anti-inflammatory, antihyperalgesic and antinociceptive properties in different animal models. The present study investigated the contribution of glutamatergic system in the antinociception elicited by (-)-linalool in mice. Nociceptive response was characterized by the time that the animal spent licking the injected hind paw or biting the target organ following glutamate receptor agonist injections. (-)-Linalool administered by intraperitoneal (i.p., 10-200 mg/kg), oral (p.o., 5-100 mg/kg) or intrathecal (i.t., 0.1-3 microg/site) routes dose-dependently inhibited glutamate-induced nociception (20 micromol/paw, pH 7.4) with ID(50) values of 139.1 mg/kg; 34.6 mg/kg; and 0.9 microg/site, with inhibitions of 70+/-4; 72+/-7 and 74+/-8%, respectively. However, the intraplantar injection of (-)-linalool partially (49+/-9%) inhibited glutamate-induced nociception. Furthermore, (-)-linalool (200 mg/kg) given i.p. also reduced significantly the biting response caused by intrathecal injection of glutamate (30 microg/site), AMPA (25 ng/site), SP (135 ng/site), NMDA (25 ng/site) and kainate (23.5 ng/site), with inhibitions of 89+/-6%, 73+/-11%, 85+/-4%, 98+/-2% and 52+/-15%, respectively. However, (-)-linalool did not inhibit nociception induced by intrathecal injection of trans-ACPD (8.6 microg/site). Taken together, these results provide experimental evidences indicating that (-)-linalool produce marked antinociception against glutamate induced pain in mice, possible due mechanisms operated by ionotropic glutamate receptors, namely AMPA, NMDA and kainate.

Antinociceptive properties of diphenyl diselenide: Evidences for the mechanism of action

The present study examined the acute toxicity and antinociceptive effects of diphenyl diselenide (PhSe) 2, given orally (p.o.), in chemical and thermical models of pain in mice. Diphenyl diselenide (7.8–312 mg/kg, p.o.) did not cause mortality. This compound did not change plasma AST (aspartate aminotransferase) and ALT (alanine aminotransferase) activities as well as urea and creatinine levels in mice after 72 h of exposure. Diphenyl diselenide (1–100 mg/kg, p.o.) inhibited acetic acid-, capsaicin-, glutamate-, bradykinin(BK)- and phorbol myristate acetate (PMA)-induced pain. Diphenyl diselenide also reduced glutamate-, bradykinin-, PMA-induced paw oedema formation. Moreover, diphenyl diselenide caused a significant increase in tail-immersion response latency time. Diphenyl diselenide co-injected subplantarly in association with glutamate-induced a significant reduction of the licking and in the paw oedema formation induced by glutamate. The local pre-treatment of mice with l-arginine, intraplantarly, restored antinociception caused by diphenyl diselenide or N G-nitro- l-arginine methyl ester ( l-NAME) when analyzed against glutamate-induced nociception. The pre-treatment of mice with dithiothreitol (DTT) intraplantarly restored local antinociception caused by diphenyl diselenide or 5,5′-dithio-bis-(2-nitrobenzoic acid) (DTNB) when analyzed against glutamate-induced nociception. These results indicate that diphenyl diselenide produced antinociception in several models of pain through mechanisms that involve an interaction with not only nitrergic system but also via interaction with redox modulatory sites of glutamate receptors.

Evidence for the involvement of glutamatergic system in the antinociceptive effect of ascorbic acid

This study examined the role of glutamatergic system in the ascorbic acid (AA)-induced antinociception in chemical behavioural models of nociception in mice. AA (0.3–10 mg/kg, i.p.) produced significant inhibition of both phases of formalin-induced licking, with mean ID 50 values of 4.0 and 3.2 mg/kg and inhibitions of 56 ± 4 and 60 ± 7% for the early and second phase of the nociception caused by formalin, respectively. AA (1–5 mg/kg, i.p.) also produced significant inhibition of glutamate-induced nociception with mean ID 50 value of 2.1 mg/kg and inhibition of 66 ± 5%. Furthermore, AA (3 mg/kg, i.p.) caused marked inhibition of nociceptive response induced by intrathecal injection of glutamate, NMDA, AMPA, kainate and substance P, with inhibitions of 49 ± 9, 42 ± 7, 34 ± 8, 38 ± 5 and 65 ± 8%, respectively. In contrast, AA at the same dose did not affect the biting response induced by the metabotropic agonist trans-ACPD. Taken together, present results indicate that AA, at low systemic doses, produces a rapid onset and consistent antinociception in mice when assessed in several models of chemical nociception, an action that is likely mediated by an interaction with ionotropic, but not metabotropic, glutamate receptors.

The role of neuropeptides and capsaicin-sensitive fibres in glutamate-induced nociception and paw oedema in mice

This study sought to establish whether sensory neuropeptides and the capsaicin-sensitive fibres are involved in the nociception and oedema formation caused by intraplantar (i.pl.) injection of glutamate into the mouse paw. The i.pl. co-injection of the selective neurokinin (NK) NK 2 (SR 48968, 0.05–0.5 nmol/paw), and to a lesser extent the selective NK 1 (FK 888, 0.25–1.0 nmol/paw) receptor antagonists, resulted in a significant inhibition of glutamate-induced nociception. The percentages of inhibition were 82 and 37%, respectively. In contrast, the selective NK 3 receptor antagonist (SR 142801, 0.25–1.0 nmol/paw) failed to significantly affect glutamate-induced nociception. SR 48968, but not FK 888 or SR 142801, significantly inhibited (36%) glutamate-induced paw oedema formation. The i.pl. injection of kinin B 1 receptor antagonist des-Arg 9-[Leu 8]-BK (0.2–0.8 nmol/paw), but not the B 2 receptor antagonist HOE 140 (1.0–4.0 nmol/paw), together with glutamate, also inhibited glutamate-induced nociception (53%) in a graded manner, without affecting glutamate-induced paw oedema. The i.pl. co-injection of the calcitonin gene-related peptide (CGRP) receptor antagonist CGRP 8–37 (1 nmol/paw) failed to significantly inhibit glutamate-induced nociception or oedema. Finally, neonatal-capsaicin (50 mg/kg, s.c.) treatment inhibited glutamate-induced nociception by 69% and to a lesser extent glutamate-mediated oedema formation (30%). Collectively, the current results indicate that the nociception caused by i.pl. injection of glutamate in mice is clearly mediated by capsaicin-sensitive fibres and by release of neurokinins from sensory neurones that activate NK 2 receptors and to a lesser extent NK 1 receptors. Furthermore, kinins acting at B 1 (but not at B 2) receptors also largely account for glutamate-mediated nociceptive behaviour response. In contrast, glutamate-induced paw oedema seems to be primarily mediated via activation of NK 2 receptors and stimulation of capsaicin-sensitive C-fibres. CGRP receptors do not seem to be involved in either of the glutamate responses.