Behavioural pharmacology
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Behavioural pharmacology · Apr 2014
In-vivo pharmacological evaluation of the CB1-receptor allosteric modulator Org-27569.
Several allosteric modulators (AMs) of the CB1 receptor have been characterized in vitro, including Org27569, which enhances CB1-specific binding of [H]CP55,940, but behaves as an insurmountable CB1-receptor antagonist in several biochemical assays. Although a growing body of research has investigated the molecular actions of this unusual AM, it is unknown whether these actions translate to the whole animal. The purpose of the present study was to determine whether Org27569 would produce effects in well-established mouse behavioral assays sensitive to CB1 orthosteric agonists and antagonists. ⋯ Org27569 did not elicit CB1-mediated effects alone and lacked efficacy in altering antinociceptive, cataleptic, and hypothermic actions of the orthosteric agonists anandamide, CP55,940, and Δ-tetrahydrocannabinol. Moreover, it did not alter the discriminative stimulus effects of anandamide in FAAH-deficient mice or Δ-tetrahydrocannabinol in wild-type mice in the drug discrimination paradigm. These findings question the utility of Org27569 as a 'gold standard' CB1 AM and underscore the need for the development of CB1 AMs with pharmacology that translates from the molecular level to the whole animal.
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Behavioural pharmacology · Apr 2014
Assessment of thermal sensitivity in rats using the thermal place preference test: description and application in the study of oxaliplatin-induced acute thermal hypersensitivity and inflammatory pain models.
Thermal sensitivity is an essential characteristic of some painful states, including oxaliplatin-induced neuropathy. The thermal place preference test (TPPT) was designed to finely assess thermal sensitivity in rodents. The TPPT monitors the time spent by unrestrained rodents on a test plate at fixed temperatures (5-50°C) compared with an adjacent reference plate at a neutral temperature (25°C). ⋯ When compared with control animals, oxaliplatin-treated rats showed thermal hypersensitivity at 12, 20 and 35°C, and carrageenan-treated rats showed thermal hypersensitivity at 15 and 45°C. Duloxetine (2.5 mg/kg, intraperitoneal) reversed oxaliplatin-induced cold hypersensitivity (20°C) and morphine (1 mg/kg, intravenous) reversed carrageenan-induced heat hypersensitivity (45°C). We conclude that the TPPT enables a fine-grained assessment of thermal sensitivity that is relevant to the pathophysiological exploration of animal pain models and to the pharmacological assessment of analgesic drugs.
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Behavioural pharmacology · Apr 2014
Intraganglionar resiniferatoxin prevents orofacial inflammatory and neuropathic hyperalgesia.
Trigeminal ganglion C-fiber neurons bearing transient receptor potential vanilloid-1 (TRPV1) channels are selectively destroyed by resiniferatoxin (RTX), a potent capsaicin analogue. The current study assessed the effect of an RTX injection (200 ng/4 μl) into the trigeminal ganglion in inflammatory and neuropathic rat models of orofacial thermal hyperalgesia. Intraganglionar RTX injection resulted in trigeminal ganglion C-fiber deletion, which was confirmed by the capsaicin eye wipes test, performed 6 days after the injection. ⋯ However, orofacial heat and cold hyperalgesia, induced by carrageenan injected into the upper lip (50 µg/50 μl), was abolished by previous intraganglionar RTX treatment. In addition, the development of orofacial heat and cold hyperalgesia after constriction of the infraorbital nerve was prevented by previous RTX treatment. Thus, trigeminal ganglion neurons expressing TRPV1 are crucial for the development of orofacial inflammatory and neuropathic thermal hyperalgesia.
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Behavioural pharmacology · Apr 2014
Analgesic efficacy of small-molecule angiotensin II type 2 receptor antagonists in a rat model of antiretroviral toxic polyneuropathy.
Individuals infected with the HIV and taking certain antiretroviral drugs to suppress viral replication have a high prevalence of neuropathic pain that is not alleviated by analgesic/adjuvant drugs that are often efficacious for the relief of other types of neuropathic pain. There is therefore a great need for new analgesics to alleviate the pain of antiretroviral toxic neuropathy (ATN). Small-molecule angiotensin II type 2 receptor (AT2R) antagonists, with ≥1000-fold selectivity over the angiotensin II type 1 receptor, produced analgesia in the chronic constriction injury of the sciatic nerve rat model of peripheral nerve trauma. ⋯ Single intraperitoneal bolus doses of EMA200 (0.3-10 mg/kg) induced dose-dependent analgesia in ddC-rats; the mean ED50 was 3.2 mg/kg. Twice-daily intraperitoneal administration of EMA300 at 30 mg/kg to ddC-rats for 3 days produced significant analgesia on days 2 and 3 of the treatment period. Therefore, small-molecule AT2R antagonists should be investigated further as novel analgesics for the relief of ATN.
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Behavioural pharmacology · Apr 2014
Effects of the fatty acid amide hydrolase inhibitor URB597 on pain-stimulated and pain-depressed behavior in rats.
Cannabinoid receptor (CBR) agonists produce antinociception in conventional preclinical assays of pain-stimulated behavior but are not effective in preclinical assays of pain-depressed behavior. Fatty acid amide hydrolase (FAAH) inhibitors increase physiological levels of the endocannabinoid anandamide, which may confer improved efficacy and safety relative to direct CBR agonists. To further evaluate FAAH inhibitors as candidate analgesics, this study assessed the effects of the FAAH inhibitor URB597 in assays of acute pain-stimulated and pain-depressed behavior in male Sprague-Dawley rats. ⋯ Conversely, in the assay of acid-depressed intracranial self-stimulation, URB597 produced a delayed, partial and non-CBR-mediated antinociceptive effect. The antinociceptive dose of URB597 (10 mg/kg) increased plasma and brain anandamide levels. These results suggest that URB597 produces antinociception in these models of 'pain stimulated' and 'pain depressed' behavior, but with different rates of onset and differential involvement of CBRs.