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.

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.

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).

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 æ-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 æg/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 æg/paw) in a peripherally mediated and dose-dependent fashion (17.3, 45.3 and 62.6 percent, respectively). The selective blockers of ATP-sensitive K+ channels glibenclamide (40, 80 and 160 æg/paw) and tolbutamide (80, 160 and 240 æg/paw) dose dependently antagonized the antinociception induced by fentanyl (1.5 æg/paw). In contrast, the effect of fentanyl was unaffected by the large conductance Ca2+-activated K+ channel blocker ChTX (2 æg/paw), the small conductance Ca2+-activated K+ channel blocker apamin (10 æg/paw), or the non-specific K+ channel blocker TEA (150 æg/paw), 4-AP (50 æg/paw), and cesium (250 æg/paw). These results extend previously reported data on the peripheral analgesic effect of morphine and fentanyl, suggesting for the first time that the peripheral æ-opioid receptor-mediated antinociceptive effect of fentanyl depends on activation of ATP-sensitive, but not other, K+ channels.

Ginseng administration protects skeletal muscle from oxidative stress induced by acute exercise in rats

Enzymatic activity was analyzed in the soleus, gastrocnemius (red and white) and plantaris muscles of acutely exercised rats after long-term administration of Panax ginseng extract in order to evaluate the protective role of ginseng against skeletal muscle oxidation. Ginseng extract (3, 10, 100, or 500 mg/kg) was administered orally for three months to male Wistar rats weighing 200 ± 50 g before exercise and to non-exercised rats (N = 8/group). The results showed a membrane stabilizing capacity of the extract since mitochondrial function measured on the basis of citrate synthase and 3-hydroxyacyl-CoA dehydrogenase activities was reduced, on average, by 20 percent (P < 0.05) after exercise but the activities remained unchanged in animals treated with a ginseng dose of 100 mg/kg. Glutathione status did not show significant changes after exercise or treatment. Lipid peroxidation, measured on the basis of malondialdehyde levels, was significantly higher in all muscles after exercise, and again was reduced by about 74 percent (P < 0.05) by the use of ginseng extract. The administration of ginseng extract was able to protect muscle from exercise-induced oxidative stress irrespective of fiber type.

The effect of L-arginine on guinea-pig and rabbit airway smooth muscle function in vitro

We have investigated the effects of L-arginine, D-arginine and L-lysine on airway smooth muscle responsiveness to spasmogens in vitro. Both L-arginine and D-arginine (100 mM) significantly reduced the contractile potency and maximal contractile response to histamine but not to methacholine or potassium chloride in guinea-pig epithelium-denuded isolated trachea. Similarly, the contractile response to histamine was significantly reduced by L-arginine (100 mM) in rabbit epithelium-denuded isolated bronchus. The amino acid L-lysine (100 mM) failed to significantly alter the contractile potency of histamine in guinea-pig isolated trachea (P> 0.05). In guinea-pig isolated trachea precontracted with histamine, both L-arginine and D-arginine produced a concentration-dependent relaxation which was not significantly altered by epithelium removal or by the presence of the nitric oxide synthase inhibitor, N G -nitro L-arginine methyl ester (L-NAME; 50 µM). Thus, at very high concentrations, arginine exhibit a non-competitive antagonism of histamine-induced contraction of isolated airway preparations that was independent of the generation of nitric oxide and was not dependent on charge. These observations confirm previous studies of cutaneous permeability responses and of contractile responses of guinea-pig isolated ileal smooth muscle. Taken together, the data suggest that high concentrations of arginine can exert an anti-histamine effect

Morphological and cytochemical characterization of cell types of the adenohypophysis of Manjuba, Anchoviella lepidentostole (Fowler, 1911) (Osteichthyes, Engraulidae)

A hipófise de Anchoviella lepidentostole apresenta-se dividida em neuro-hipófise e adeno-hipófise, sendo que a caracterizaçäo morfológica e citoquímica dos tipos celulares desta regiäo foi a proposta deste trabalho. A adeno-hipófise divide-se em pars intermedia (PI) e pars distalis (PD), sendo que esta última se divide em pars distalis rostralis (PDR) e pars distalis proximalis (PDP). As células da PDR organizam-se em folículos. No epitélio folicular foram caracterizados quatro tipos celulares: I-PDR (basófilo), II-PDR (positivo à hematoxilina-chumbo/HPb+), III-PDR (PAS+, AB pH2,5+ e AF+), e IV-PDR (acidófilas). A PDP possui dois tipos celulares: I-PDP (PAS+, AB pH2,5+ e AF+) e II-PDP (acidófilas). Na PI também foram caracterizados dois tipos celulares: I-PI (HPb+) e II-PI (cromófobo aos métodos empregados)

Atividade colinesterasica no plasma e em eritrocitos de portadores de megacolo chagasico. / Plasma and erythrocyte cholinesterase activity of patients with Chagas' megacolon

A atividade colinesterasica foi medida no plasma e em eritrocitos de 32 individuos.Em 16 pacientes, seguramente portadores de megacolo chagasico, os niveis de colinesterase no plasma (1.540 +/- 318 UI/L) e nos eritrocitos (53,2 +/- 9,1 UI/g Hb) estavam significativamente diminuidos, quando comparados com os niveis enzimaticos no plasma (2.554 +/- 826 UI/L) e nos eritrocitos (63,6 +/- 11UI/g Hb) do grupo controle (n = 16). Os resultados mostraram um paralelismo entre a atividade colinesterasica sistemica e os achados histopatologicos