Analgesia and pain: Dual effect of dopamine on the peripheral nociceptive system is dependent on D2-or D1-like receptor activation.

In this study, a pharmacological approach, together with the paw pressure test, was used to investigate the role of dopamine and its receptors in the peripheral processing of the nociceptive response in mice. Initially, the administration of dopamine (5, 20, and 80 ng/paw) in the hind paw of male Swiss mice (30-40 g) promoted antinociceptive effects in a dose-dependent manner. This was considered a peripheral effect, as it did not produce changes in the nociceptive threshold of the contralateral paw. The D2, D3, and D4 dopamine receptor antagonists remoxipride (4 µg/paw), U99194 (16 µg/paw), and L-745,870 (16 µg/paw), respectively, reversed the dopamine-mediated antinociception in mice with PGE2-induced hyperalgesia. The D1 and D5 dopamine receptor antagonists SKF 83566 (2 µg/paw) and SCH 23390 (1.6 µg/paw), respectively, did not alter dopamine antinociception. In contrast, dopamine at higher doses (0.1, 1, and 10 µg/paw) caused hyperalgesia in the animals, and the D1 and D5 receptor antagonists reversed this pronociceptive effect (10 µg/paw), whereas the D2 receptor antagonist remoxipride did not. Our data suggest that dopamine has a dual effect that depends on the dose, as it causes peripheral antinociceptive effects at small doses via the activation of D2-like receptors and nociceptive effects at higher doses via the activation of D1-like receptors.

Kahweol, a natural diterpene from coffee, induces peripheral antinociception by endocannabinoid system activation.

Kahweol is a compound derived from coffee with reported antinociceptive effects. Based on the few reports that exist in the literature regarding the mechanisms involved in kahweol-induced peripheral antinociceptive action, this study proposed to investigate the contribution of the endocannabinoid system to the peripheral antinociception induced in rats by kahweol. Hyperalgesia was induced by intraplantar injection of prostaglandin E2(PGE2) and was measured with the paw pressure test. Kahweol and the drugs to test the cannabinoid system were administered locally into the right hind paw. The endocannabinoids were purified by open-bed chromatography on silica and measured by LC-MS. Kahweol (80 µg/paw) induced peripheral antinociception against PGE2-induced hyperalgesia. This effect was reversed by the intraplantar injection of the CB1 cannabinoid receptor antagonist AM251 (20, 40, and 80 µg/paw), but not by the CB2 cannabinoid receptor antagonist AM630 (100 µg/paw). Treatment with the endocannabinoid reuptake inhibitor VDM11 (2.5 µg/paw) intensified the peripheral antinociceptive effect induced by low-dose kahweol (40 µg/paw). The monoacylglycerol lipase (MAGL) inhibitor, JZL184 (4 µg/paw), and the dual MAGL/fatty acid amide hydrolase (FAAH) inhibitor, MAFP (0.5 µg/paw), potentiated the peripheral antinociceptive effect of low-dose kahweol. Furthermore, kahweol increased the levels of the endocannabinoid anandamide, but not of the other endocannabinoid 2-arachidonoylglycerol nor of anandamide-related N-acylethanolamines, in the plantar surface of the rat paw. Our results suggested that kahweol induced peripheral antinociception via anandamide release and activation of CB1 cannabinoid receptors and this compound could be used to develop new drugs for pain relief.

Kahweol, a natural diterpene from coffee, induces peripheral antinociception by endocannabinoid system activation

Kahweol is a compound derived from coffee with reported antinociceptive effects. Based on the few reports that exist in the literature regarding the mechanisms involved in kahweol-induced peripheral antinociceptive action, this study proposed to investigate the contribution of the endocannabinoid system to the peripheral antinociception induced in rats by kahweol. Hyperalgesia was induced by intraplantar injection of prostaglandin E2(PGE2) and was measured with the paw pressure test. Kahweol and the drugs to test the cannabinoid system were administered locally into the right hind paw. The endocannabinoids were purified by open-bed chromatography on silica and measured by LC-MS. Kahweol (80 µg/paw) induced peripheral antinociception against PGE2-induced hyperalgesia. This effect was reversed by the intraplantar injection of the CB1 cannabinoid receptor antagonist AM251 (20, 40, and 80 μg/paw), but not by the CB2 cannabinoid receptor antagonist AM630 (100 μg/paw). Treatment with the endocannabinoid reuptake inhibitor VDM11 (2.5 μg/paw) intensified the peripheral antinociceptive effect induced by low-dose kahweol (40 μg/paw). The monoacylglycerol lipase (MAGL) inhibitor, JZL184 (4 μg/paw), and the dual MAGL/fatty acid amide hydrolase (FAAH) inhibitor, MAFP (0.5 μg/paw), potentiated the peripheral antinociceptive effect of low-dose kahweol. Furthermore, kahweol increased the levels of the endocannabinoid anandamide, but not of the other endocannabinoid 2-arachidonoylglycerol nor of anandamide-related N-acylethanolamines, in the plantar surface of the rat paw. Our results suggested that kahweol induced peripheral antinociception via anandamide release and activation of CB1 cannabinoid receptors and this compound could be used to develop new drugs for pain relief.

The synthetic peptide PnPP-19 induces peripheral antinociception via activation of NO/cGMP/KATP pathway: Role of eNOS and nNOS.

BACKGROUND: and purpose: The peptide PnPP-19, derived from the spider toxin PnTx2-6 (renamed as δ-CNTX-Pn1c), potentiates erectile function by activating the nitrergic system. Since NO has been studied as an antinociceptive molecule and PnPP-19 is known to induce peripheral antinociception, we intended to evaluate whether PnPP-19 could induce peripheral antinociception through activation of this pathway. EXPERIMENTAL APPROACH: Nociceptive thresholds were measured by paw pressure test. PGE2 (2 µg/paw) was administered intraplantarly together with PnPP-19 and inhibitors/blockers of NOS, guanylyl cyclase and KATP channels. The nitrite concentration was accessed by Griess test. The expression and phosphorylation of eNOS and nNOS were determined by western blot. KEY RESULTS: PnPP-19 (5, 10 and 20 µg/paw) induced peripheral antinociception in rats. Administration of NOS inhibitor (L-NOarg), selective nNOS inhibitor (L-NPA), guanylyl cyclase inhibitor (ODQ) and the blocker of KATP (glibenclamide) partially inhibited the antinociceptive effect of PnPP-19 (10 µg/paw). Tissue nitrite concentration increased after PnPP-19 (10 µg/paw) administration. Expression of eNOS and nNOS remained the same in all tested groups, however the phosphorylation of nNOS Ser852 (inactivation site) increased and phosphorylation of eNOS Ser1177 (activation site) decreased after PGE2 injection. Administration of PnPP-19 reverted this PGE2-induced effect. CONCLUSIONS AND IMPLICATIONS: The peripheral antinociceptive effect induced by PnPP-19 is resulting from activation of NO-cGMP-KATP pathway. Activation of eNOS and nNOS might be required for such effect. Our results suggest PnPP-19 as a new drug candidate to treat pain and reinforce the importance of nNOS and eNOS activation, as well as endogenous NO release, for induction of peripheral antinociception.

PnPP-19, a spider toxin peptide, induces peripheral antinociception through opioid and cannabinoid receptors and inhibition of neutral endopeptidase.

BACKGROUND AND PURPOSE: The synthetic peptide PnPP-19 has been studied as a new drug candidate to treat erectile dysfunction. However, PnTx2-6, the spider toxin from which the peptide was designed, induces hyperalgesia. Therefore, we intended to investigate the role of PnPP-19 in the nociceptive pathway. EXPERIMENTAL APPROACH: Nociceptive thresholds were measured by paw pressure test. PnPP-19 was administered intraplantarly alone or with selective cannabinoid or opioid receptor antagonists. The hydrolysis of PnPP-19 by neutral endopeptidase (NEP) (EC 3.4.24.11), an enzyme that cleaves enkephalin, was monitored by HPLC and the cleavage sites were deduced by LC-MS. Inhibition by PnPP-19 and Leu-enkephalin of NEP enzyme activity was determined spectrofluorimetrically. KEY RESULTS: PnPP-19 (5, 10 and 20 µg per paw) induced peripheral antinociception in rats. Specific antagonists of µ opioid receptors (clocinnamox), δ opioid receptors (naltrindole) and CB1 receptors (AM251) partly inhibited the antinociceptive effect of PnPP-19. Inhibition of fatty acid amide hydrolase by MAFP or of anandamide uptake by VDM11 enhanced PnPP-19-induced antinociception. NEP cleaved PnPP-19 only after a long incubation, and Ki values of 35.6 ± 1.4 and 14.6 ± 0.44 µmol·L(-1) were determined for PnPP-19 and Leu-enkephalin respectively as inhibitors of NEP activity. CONCLUSIONS AND IMPLICATIONS: Antinociception induced by PnPP-19 appears to involve the inhibition of NEP and activation of CB1, µ and δ opioid receptors. Our data provide a greater understanding of the antinociceptive effects of PnPP-19. This peptide could be useful as a new antinociceptive drug candidate.

Participation of cannabinoid receptors in peripheral nociception induced by some NSAIDs

Nonsteroidal anti-inflammatory drugs (NSAIDs) have been used extensively to control inflammatory pain. Several peripheral antinociceptive mechanisms have been described, such as opioid system and NO/cGMP/KATP pathway activation. There is evidence that the cannabinoid system can also contribute to the in vivo pharmacological effects of ibuprofen and indomethacin. However, there is no evidence of the involvement of the endocannabinoid system in the peripheral antinociception induced by NSAIDs. Thus, the aim of this study was to investigate the participation of the endocannabinoid system in the peripheral antinociceptive effect of NSAIDs. All experiments were performed on male Wistar rats (160-200 g; N = 4 per group). Hyperalgesia was induced by a subcutaneous intraplantar (ipl) injection of prostaglandin E2 (PGE2, 2 μg/paw) in the rat’s hindpaw and measured by the paw pressure test 3 h after injection. The weight in grams required to elicit a nociceptive response, paw flexion, was determined as the nociceptive threshold. The hyperalgesia was calculated as the difference between the measurements made before and after PGE2, which induced hyperalgesia (mean = 83.3 ± 4.505 g). AM-251 (80 μg/paw) and AM-630 (100 μg/paw) were used as CB1 and CB2 cannabinoid receptor antagonists, respectively. Ipl injection of 40 μg dipyrone (mean = 5.825 ± 2.842 g), 20 μg diclofenac (mean = 4.825 ± 3.850 g) and 40 μg indomethacin (mean = 6.650 ± 3.611 g) elicited a local peripheral antinociceptive effect. This effect was not antagonized by ipl CB1 cannabinoid antagonist to dipyrone (mean = 5.00 ± 0.9815 g), diclofenac (mean = 2.50 ± 0.8337 g) and indomethacin (mean = 6.650 ± 4.069 g) or CB2 cannabinoid antagonist to dipyrone (mean = 1.050 ± 6.436 g), diclofenac (mean = 6.675 ± 1.368 g) and indomethacin (mean = 2.85 ± 5.01 g). Thus, cannabinoid receptors do not seem to be involved in the peripheral antinociceptive mechanism of the NSAIDs dipyrone, diclofenac and indomethacin.

Participation of cannabinoid receptors in peripheral nociception induced by some NSAIDs.

Nonsteroidal anti-inflammatory drugs (NSAIDs) have been used extensively to control inflammatory pain. Several peripheral antinociceptive mechanisms have been described, such as opioid system and NO/cGMP/KATP pathway activation. There is evidence that the cannabinoid system can also contribute to the in vivo pharmacological effects of ibuprofen and indomethacin. However, there is no evidence of the involvement of the endocannabinoid system in the peripheral antinociception induced by NSAIDs. Thus, the aim of this study was to investigate the participation of the endocannabinoid system in the peripheral antinociceptive effect of NSAIDs. All experiments were performed on male Wistar rats (160-200 g; N = 4 per group). Hyperalgesia was induced by a subcutaneous intraplantar (ipl) injection of prostaglandin E2 (PGE2, 2 µg/paw) in the rat's hindpaw and measured by the paw pressure test 3 h after injection. The weight in grams required to elicit a nociceptive response, paw flexion, was determined as the nociceptive threshold. The hyperalgesia was calculated as the difference between the measurements made before and after PGE2, which induced hyperalgesia (mean = 83.3 ± 4.505 g). AM-251 (80 µg/paw) and AM-630 (100 µg/paw) were used as CB1 and CB2 cannabinoid receptor antagonists, respectively. Ipl injection of 40 µg dipyrone (mean = 5.825 ± 2.842 g), 20 µg diclofenac (mean = 4.825 ± 3.850 g) and 40 µg indomethacin (mean = 6.650 ± 3.611 g) elicited a local peripheral antinociceptive effect. This effect was not antagonized by ipl CB1 cannabinoid antagonist to dipyrone (mean = 5.00 ± 0.9815 g), diclofenac (mean = 2.50 ± 0.8337 g) and indomethacin (mean = 6.650 ± 4.069 g) or CB2 cannabinoid antagonist to dipyrone (mean = 1.050 ± 6.436 g), diclofenac (mean = 6.675 ± 1.368 g) and indomethacin (mean = 2.85 ± 5.01 g). Thus, cannabinoid receptors do not seem to be involved in the peripheral antinociceptive mechanism of the NSAIDs dipyrone, diclofenac and indomethacin.

Participation of endogenous opioids in the antinociception induced by resistance exercise in rats

Exercise is a low-cost intervention that promotes health and contributes to the maintenance of the quality of life. The present study was designed to investigate the influence of different resistance exercise protocols on the nociceptive threshold of rats. Female Wistar rats were used to perform exercises in a weight-lifting exercise model. The following groups were examined (N = 6 per group): untrained rats (control group); an acute protocol group consisting of rats submitted to 15 sets of 15 repetitions of resistance exercise (acute group); rats exercised with 3 sets of 10 repetitions, three times per week for 12 weeks (trained group), and a group consisting of trained rats that were further submitted to the acute protocol (trained-acute group). The nociceptive threshold was measured by the paw-withdrawal test, in which the withdrawal threshold (escape reaction) was measured by an apparatus applying force to the plantar surface of the animal paw. The opioid antagonist naloxone (2 mg/kg) was administered subcutaneously 10 min before the exercise protocols. The trained group demonstrated antinociception only up to day 45 of the 12-week training period. A significant increase (37 percent, P < 0.05) in the nociceptive threshold was produced immediately after exercise, decreasing to 15 percent after 15 min, when the acute exercise protocol was used. Naloxone reversed this effect. These data show that the acute resistance exercise protocol was effective in producing antinociception for 15 min. This antinociceptive effect is mediated by the activation of opioid receptors.

Participation of endogenous opioids in the antinociception induced by resistance exercise in rats.

Exercise is a low-cost intervention that promotes health and contributes to the maintenance of the quality of life. The present study was designed to investigate the influence of different resistance exercise protocols on the nociceptive threshold of rats. Female Wistar rats were used to perform exercises in a weight-lifting exercise model. The following groups were examined (N = 6 per group): untrained rats (control group); an acute protocol group consisting of rats submitted to 15 sets of 15 repetitions of resistance exercise (acute group); rats exercised with 3 sets of 10 repetitions, three times per week for 12 weeks (trained group), and a group consisting of trained rats that were further submitted to the acute protocol (trained-acute group). The nociceptive threshold was measured by the paw-withdrawal test, in which the withdrawal threshold (escape reaction) was measured by an apparatus applying force to the plantar surface of the animal paw. The opioid antagonist naloxone (2 mg/kg) was administered subcutaneously 10 min before the exercise protocols. The trained group demonstrated antinociception only up to day 45 of the 12-week training period. A significant increase (37%, P < 0.05) in the nociceptive threshold was produced immediately after exercise, decreasing to 15% after 15 min, when the acute exercise protocol was used. Naloxone reversed this effect. These data show that the acute resistance exercise protocol was effective in producing antinociception for 15 min. This antinociceptive effect is mediated by the activation of opioid receptors.

Role of systemic and local administration of selective inhibitors of cyclo-oxygenase 1 and 2 in an experimental model of periodontal disease in rats.

BACKGROUND AND OBJECTIVE: Periodontal disease is an inflammatory condition of tooth-supporting tissues. Arachidonic acid metabolites have been implicated in development of periodontal disease, especially those derived from the cyclo-oxygenase (COX) pathway. This study investigated the role of inhibitors of cyclo-oxygenases (COX-1 and COX-2) in a model of periodontal disease in rats. MATERIAL AND METHODS: A ligature was placed around the molar of rats. Losses of fiber attachment and of alveolar bone were measured morphometrically in histologically prepared sections. Infiltration of cells into gingival tissue surrounding the ligated tooth was also determined. RESULTS: Systemic and local administration of non-selective and selective COX-2 inhibitors, preventively, resulted in significant reduction of the losses of fiber attachment and alveolar bone, as well as decreased leukocyte numbers in gingival tissue. Preventive selective inhibition of COX-1 was as effective as COX-2 inhibition in reducing local fiber attachment loss and cell migration, but did not prevent alveolar bone loss. CONCLUSION: Our results provide evidence for participation of COX-1 and COX-2 in early stages of periodontal disease in rats. Furthermore, local administration of COX inhibitors reduced the signs of periodontal disease to the same extent as systemic treatment. Therapeutic approaches incorporating locally delivered anti-inflammatory drugs could be of benefit for patients suffering from periodontal disease.

Crucial role of peripheral kappa-opioid receptors in a model of periodontal disease in rats.

BACKGROUND AND OBJECTIVE: Periodontal disease is a chronic inflammatory condition of the tooth supporting tissues, the periodontium. Opioids have been shown to account for the relief of various chronic and acute inflammatory conditions. The aim of the present study was to investigate the participation of peripheral opioid receptors in development of periodontal disease. MATERIAL AND METHODS: Morphine and selective agonists and antagonists of opioid receptors were used in an experimental model of ligature-induced periodontal disease in rats. To evaluate the development of disease, the loss of fiber attachment, alveolar bone and number of cells in periodontal tissues were assessed. Measurements of these indicators were obtained by morphometric analysis of histological sections of periodontal-diseased tissues stained with hematoxylin and eosin. RESULTS: Local administration of either morphine or a selective kappa-opioid agonist for three consecutive days from the onset of periodontal disease reduced the loss of periodontal tissues, without changing the number of leukocytes in inflamed periodontium. Nor-binaltorphimine, a selective kappa-antagonist, reversed the beneficial effects of both morphine and the compound U-50,488 in this model. The use of either an agonist or an antagonist of delta-opioid receptors, however, did not affect disease progression. CONCLUSION: Our results showed that the beneficial effect of opioids in periodontal disease depended mainly on the activation of specific kappa-opioid receptors located in the periphery. Activation of such receptors could be considered in the management of periodontal disease, since it would not present the classical central side-effects associated with opioid use.

Opioidergic orofacial antinociception induced by electroacupuncture at acupoint St36.

The participation of opioids in the antinociceptive effect of electroacupuncture was evaluated in terms of nociception produced by thermal stimuli applied to the face of male Wistar rats, weighing 180-230 g. Electrical stimulation (bipolar and asymmetric square wave with 0.5 mA intensity for 20 min) of acupoint St36, located in the anterior tibial muscle 10 mm distal to the knee joint, induced antinociception in the present model, which was maintained for 150 min. Acupoint LI4, located in the junction of the first and second metacarpal bones, did not achieve antinociception at any frequency studied (5 Hz: 1.7 +/- 0.1; 30 Hz: 1.8 +/- 0.1; 100 Hz: 1.7 +/- 0.1 vs 1.4 +/- 0.2). The antinociception obtained by stimulation of acupoint St36 was only achieved when high frequency 100 Hz (3.0 +/- 0.2 vs 1.0 +/- 0.1) was used, and not with 5 or 30 Hz (1.2 +/- 0.2 and 0.7 +/- 0.1 vs 1.0 +/- 0.1). The antinociceptive effect of acupuncture occurred by opioid pathway activation, since naloxone (1 and 2 mg/kg, subcutaneously) antagonized it (1.8 +/- 0.2 and 1.7 +/- 0.2 vs 3.0 +/- 0.1).

Opioidergic orofacial antinociception induced by electroacupuncture at acupoint St36

The participation of opioids in the antinociceptive effect of electroacupuncture was evaluated in terms of nociception produced by thermal stimuli applied to the face of male Wistar rats, weighing 180-230 g. Electrical stimulation (bipolar and asymmetric square wave with 0.5 mA intensity for 20 min) of acupoint St36, located in the anterior tibial muscle 10 mm distal to the knee joint, induced antinociception in the present model, which was maintained for 150 min. Acupoint LI4, located in the junction of the first and second metacarpal bones, did not achieve antinociception at any frequency studied (5 Hz: 1.7 ± 0.1; 30 Hz: 1.8 ± 0.1; 100 Hz: 1.7 ± 0.1 vs 1.4 ± 0.2). The antinociception obtained by stimulation of acupoint St36 was only achieved when high frequency 100 Hz (3.0 ± 0.2 vs 1.0 ± 0.1) was used, and not with 5 or 30 Hz (1.2 ± 0.2 and 0.7 ± 0.1 vs 1.0 ± 0.1). The antinociceptive effect of acupuncture occurred by opioid pathway activation, since naloxone (1 and 2 mg/kg, subcutaneously) antagonized it (1.8 ± 0.2 and 1.7 ± 0.2 vs 3.0 ± 0.1).

The mu-opioid receptor agonist morphine, but not agonists at delta- or kappa-opioid receptors, induces peripheral antinociception mediated by cannabinoid receptors.

BACKGROUND AND PURPOSE: Although participation of opioids in antinociception induced by cannabinoids has been documented, there is little information regarding the participation of cannabinoids in the antinociceptive mechanisms of opioids. The aim of the present study was to determine whether endocannabinoids could be involved in peripheral antinociception induced by activation of mu-, delta- and kappa-opioid receptors. EXPERIMENTAL APPROACH: Nociceptive thresholds to mechanical stimulation of rat paws treated with intraplantar prostaglandin E2 (PGE2, 2 microg) to induce hyperalgesia were measured 3 h after injection using an algesimetric apparatus. Opioid agonists morphine (200 microg), (+)-4-[(alphaR)-alpha-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC80) (80 microg), bremazocine (50 microg); cannabinoid receptor antagonists N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM251) (20-80 microg), 6-iodo-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indol-3-yl(4-methoxyphenyl) methanone (AM630) (12.5-100 microg); and an inhibitor of methyl arachidonyl fluorophosphonate (MAFP) (1-4 microg) were also injected in the paw. KEY RESULTS: The CB1-selective cannabinoid receptor antagonist AM251 completely reversed the peripheral antinociception induced by morphine in a dose-dependent manner. In contrast, the CB2-selective cannabinoid receptor antagonist AM630 elicited partial antagonism of this effect. In addition, the administration of the fatty acid amide hydrolase inhibitor, MAFP, enhanced the antinociception induced by morphine. The cannabinoid receptor antagonists AM251 and AM630 did not modify the antinociceptive effect of SNC80 or bremazocine. The antagonists alone did not cause any hyperalgesic or antinociceptive effect. CONCLUSIONS AND IMPLICATIONS: Our results provide evidence for the involvement of endocannabinoids, in the peripheral antinociception induced by the mu-opioid receptor agonist morphine. The release of cannabinoids appears not to be involved in the peripheral antinociceptive effect induced by kappa- and delta-opioid receptor agonists.

Antinociceptive effect from Davilla elliptica hydroalcoholic extract.

Davilla elliptica St Hill (Dilleniaceae) is widely used for multiple purposes in Brazil. The aim of this study was to verify the pharmacological support of this folk use and evaluate its use as antinociceptive. The hydroalcoholic extract of the stems (100-1000 mg/kg, p.o.) induced reduction of response in the formalin test inflammatory phase in mice. This antinociceptive effect does not involve the opioidergic pathway since it was not reverted by pre-treatment with naloxone nor due to myorelaxant activity since it did not affect rota-rod and tail-flick performance. Our results indicate a participation of the nitrergic pathway and may be of particular potential importance in clinical medicine, in view of the current interest in the assessment of new medicines originated from plants.

Baclofen, an agonist at peripheral GABAB receptors, induces antinociception via activation of TEA-sensitive potassium channels.

BACKGROUND AND PURPOSE: Central anti-nociceptive actions of baclofen involve activation of K+ channels. Here we assessed what types of K+ channel might participate in the peripheral anti-nociception induced by baclofen. EXPERIMENTAL APPROACH: Nociceptive thresholds to mechanical stimulation in rat paws treated with intraplantar prostaglandin E2.(PGE2) to induce hyperalgesia were measured 3 h after PGE2 injection. Other agents were also given by intraplantar injection. KEY RESULTS: Baclofen elicited a dose-dependent (15 - 240 microg per paw) anti-nociceptive effect. An intermediate dose of baclofen (60 microg) did not produce antinociception in the contralateral paw, showing its peripheral site of action. The GABAB receptor antagonist saclofen (12.5 - 100 microg per paw) antagonized, in a dose-dependent manner, peripheral antinociception induced by baclofen (60 microg), suggesting a specific effect. This antinociceptive action of baclofen was unaffected by bicuculline, GABAA receptor antagonist (80 microg per paw), or by (1,2,5,6 tetrahydropyridin-4-yl) methylphosphinic acid, GABAC receptor antagonist (20 microg per paw). The peripheral antinociception induced by baclofen (60 microg) was reversed, in a dose-dependent manner, by the voltage-dependent K+ channel blockers tetraethylammonium (7.5 - 30 microg per paw) and 4-aminopyridine (2.5 - 10 microg per paw). The blockers of other K+ channels, glibenclamide (160 microg), tolbutamide (320 microg), charybdotoxin (2 microg), dequalinium (50 microg) and caesium (500 microg) had no effect. CONCLUSIONS AND IMPLICATIONS: This study provides evidence that the peripheral antinociceptive effect of the GABAB receptor agonist baclofen results from the activation of tetraethylammonium-sensitive K+ channels. Other K+ channels appear not to be involved.

Effect of Solanum lycocarpum St. Hill on various haematological parameters in diabetic rats.

Solanum lycocarpum St. Hill (SL) is commonly used in Brazilian folk medicine. The aim of the present study was to evaluate the validity of the traditional therapeutic indication of SL as hypoglycaemic agent. The extract reduced glycemia to 92.4mg/dl in alloxan induced diabetic rats (230.5mg/dl). We also investigated the potential of SL as antioxidant (it reduced in 27% nitrate generation in diabetic animals). Our results also demonstrated that SL is not ulcerogenic and restored haemoglobin and haematocrit to normal values in diabetic animals.

Antinociceptive effect from Ipomoea cairica extract.

Ipomoea cairica L. Sweet (Convolvulaceae) is used in Brazilian folk medicine for the treatment of rheumatism and inflammations. Ipomoea cairica ethanolic extract (100, 300, 1000 and 3000 mg/kg; per os) induced dose-dependent reduction of response in the formalin test inflammatory phase in mice. The same dose range did not modify neurogenic pain in formalin test, tail-flick reflex latency, carrageenan-induced paw edema, and Rota-Rod test motor performance. From the bio-active fraction 3,5-di-O-caffeoylquinic acid and 4,5-di-O-caffeoylquinic acid were obtained. These compounds have been previously reported to have analgesic and antioxidative effects. A possible explanation for the antinociception is that somehow the compounds present in the extract reduced the release of pro-nociceptive mediators unrelated to carrageenan-induced edema, such as histamine. Interestingly, caffeoylquinic acid derivatives have been reported to inhibit histamine release on in vitro models. The isolated caffeoylquinic acids could explain, at least in part, the antinociceptive effect of Ipomoea cairica polar extract.

Protection of Panax ginseng in injured muscles after eccentric exercise.

Panax ginseng C.A. Meyer, the root of an Araliaceae plant has been shown to possess various biological effects. Ginseng treatment (100 mg kg(-1)) protected muscles from eccentric exercise injuries. It was effective in preserving mitochondrial membrane integrity and reduced nitrate concentration in vastus and rectus (46% and 26%, respectively). It also reduced carbonyl contents by approximately 27% in all the muscles studied.

Participation of ATP-sensitive K+ channels in the peripheral antinociceptive effect of fentanyl in rats.

We examined the effect of several K+ channel blockers such as glibenclamide, tolbutamide, charybdotoxin (ChTX), apamin, tetraethylammonium chloride (TEA), 4-aminopyridine (4-AP), and cesium on the ability of fentanyl, a clinically used selective micro-opioid receptor agonist, to promote peripheral antinociception. Antinociception was measured by the paw pressure test in male Wistar rats weighing 180-250 g (N = 5 animals per group). Carrageenan (250 microg/paw) decreased the threshold of responsiveness to noxious pressure (delta = 188.1 +/- 5.3 g). This mechanical hyperalgesia was reduced by fentanyl (0.5, 1.5 and 3 microg/paw) in a peripherally mediated and dose-dependent fashion (17.3, 45.3 and 62.6%, respectively). The selective blockers of ATP-sensitive K+ channels glibenclamide (40, 80 and 160 microg/paw) and tolbutamide (80, 160 and 240 microg/paw) dose dependently antagonized the antinociception induced by fentanyl (1.5 microg/paw). In contrast, the effect of fentanyl was unaffected by the large conductance Ca2+-activated K+ channel blocker ChTX (2 microg/paw), the small conductance Ca2+-activated K+ channel blocker apamin (10 microg/paw), or the non-specific K+ channel blocker TEA (150 microg/paw), 4-AP (50 microg/paw), and cesium (250 microg/paw). These results extend previously reported data on the peripheral analgesic effect of morphine and fentanyl, suggesting for the first time that the peripheral micro-opioid receptor-mediated antinociceptive effect of fentanyl depends on activation of ATP-sensitive, but not other, K+ channels.