A review of current animal models of osteoarthritis pain.

Osteoarthritis (OA) is a complex disease plagued by a significant unmet need for treatment. To date, no disease- modifying OA drugs (DMOADs) exist and the available symptom-modifying OA drugs (SMOADs) have limitations. Although a complete understanding of the mechanisms of OA pain in humans is lacking, animal models have helped provide insight into the multifaceted origin and manifestation of OA pain. Success in discovering new therapeutics will likely require reliance on good animal models. This review summarizes the animal models available for studying pain associated with OA.

Effects of ethanol on cocaine discrimination in rats.

Ethanol and cocaine are frequently abused in combination, but little is known about how the subjective effects of the two drugs interact. The ability of ethanol and other GABA(A)-active compounds to alter the discriminative stimulus effects of cocaine was tested. Male Sprague-Dawley rats were trained to discriminate cocaine (10 mg/kg ip) from saline using either single- or cumulative-dosing methods. In single-dose testing, ethanol (0.1-0.5 g/kg) dose-dependently decreased cocaine-appropriate responding following the training dose of cocaine. Ethanol (0.5 g/kg) produced a rightward shift in the cocaine cumulative dose-effect curve. Ethanol (0.1-1.0 g/kg) failed to substitute for the discriminative stimulus effects of cocaine and the higher doses (1-2 g/kg) completely suppressed responding. Indirect GABA(A) agonists diazepam (benzodiazepine site) and pentobarbital (barbiturate site) did not block the discriminative stimulus effects of cumulative doses of cocaine. The GABA(A) antagonist pentylenetetrazol (PTZ) (10-40 mg/kg) did not substitute for cocaine. These findings suggest that ethanol can modulate the discriminative stimulus effects of cocaine, and that these effects may not be mediated by the actions of ethanol at the GABA(A) receptor.

Weight loss in rats exposed to repeated acute restraint stress is independent of energy or leptin status.

Acute release of corticotropin-releasing factor (CRF) during repeated restraint (3-h restraint on each of 3 days) causes temporary hypophagia but chronic suppression of body weight in rats. Here we demonstrated that a second bout of repeated restraint caused additional weight loss, but continuing restraint daily for 10 days did not increase weight loss because the rats adapted to the stress. In these two studies serum leptin, which suppresses the endocrine response to stress, was reduced in restrained rats. Peripheral infusion of leptin before and during restraint did not prevent stress-induced weight loss, although stress-induced corticosterone release was suppressed. Restrained rats were hyperthermic during restraint, but there was no evidence that fever or elevated free interleukin-6 caused the sustained reduction in weight. Restraining food-restricted rats caused a small but significant weight loss. Food-restricted rats fed ad libitum after the end of restraint showed a blunted hyperphagia and slower rate of weight regain than their controls. These results indicate that repeated acute stress induces a chronic change in weight independent of stress-induced hypophagia and may represent a change in homeostasis initiated by repeated acute activation of the central CRF system.