Food and water were freely available until the beginning of the experiments

Food and water were freely available until the beginning of the experiments. = 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. with 9-THC as prototype, the related group of synthetic drugs and finally the endogenous eicosanoids, with anandamide as the compound most extensively studied (1). At the peripheral level, cannabinoid receptors are known to be involved in primary afferent neuron modulation, inhibiting membrane excitation and Ca2+ conductance and also increasing potassium conductance, inducing a similar antinociceptive effect. The antinociceptive effect of the endocannabinoid system has been implicated in pain models (2). Nonsteroidal anti-inflammatory drugs (NSAIDs) like dipyrone, diclofenac and indomethacin are widely prescribed for their antinociceptive and analgesic activity (3). The search for different mechanisms of NSAID-induced antinociception has greatly increased after investigators observed that inhibition of prostaglandin synthesis in the inflamed tissue is not the only pathway for this response. Previous studies have demonstrated that the opioid system and the NO/cGMP/KATP pathway could be involved in the antinociceptive mechanism of NSAIDs (4,5). There is evidence indicating that the cannabinoid system can contribute to the pharmacological effects of ibuprofen and indomethacin (6). Ghring et al. (7) have suggested that indomethacin may allow an increased synthesis of endocannabinoids from arachidonic acid by blocking cyclooxygenase (COX). The same investigators have shown that spinal pretreatment with AM-251 blocks the antinociception caused by indomethacin. However, there is no evidence of involvement Bay 41-4109 less active enantiomer of the endocannabinoid system in the peripheral antinociception induced by NSAIDs. Thus, the objective of the present study was to investigate the participation of the CB1 and CB2 cannabinoid receptors in the peripheral antinociceptive effect of the NSAIDs dipyrone, diclofenac and indomethacin. Material and Methods Animals All experiments were performed on male Wistar rats (160-200?g) from CEBIO-UFMG (Universidade Federal de Minas Gerais) housed in a temperature-controlled room (23 1C) on an automatic 12-h light/dark cycle (6:00-18:00 h). Food and water were freely available until the beginning of the experiments. Animals were used only once and sacrificed after the experiments. All animal procedures and protocols were approved by the Ethics Committee for Animal Experimentation (CETEA) of the UFMG. Measurement of hyperalgesia Hyperalgesia was induced by a subcutaneous Bay 41-4109 less active enantiomer injection of prostaglandin E2 (PGE2; 2?g) into the plantar surface of the hind paw and measured using the paw pressure Bay 41-4109 less active enantiomer test described by Randall and Selitto (8). An analgesimeter was used (Ugo-Basile, Italy) with a cone-shaped paw-presser with a rounded tip, which applies a linearly increasing force to the hind paw. The weight Bay 41-4109 less active enantiomer in grams required to elicit the nociceptive response of paw flexion was determined as the nociceptive threshold. A cutoff value of 300?g was used to reduce the possibility of damage to the paws. The nociceptive threshold was measured in the right paw and determined as the average of three consecutive trials recorded before and 3?h after PGE2 injection. The hyperalgesia was calculated as the difference between these two averages ( of nociceptive threshold) and reported in grams. Drug administration All drugs were administered by injecting a volume Bay 41-4109 less active enantiomer of 50?L/paw, with the exception Rabbit polyclonal to PDK3 of PGE2 (100?L/paw). Diclofenac (Purifarma, Brazil) and dipyrone (Sigma, USA) were dissolved in isotonic saline, while indomethacin (Sigma) was dissolved in Tris-base buffer. The CB1 and CB2 cannabinoid receptor antagonists, AM-251 (Tocris, USA) and AM-630 (Tocris) were.

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