European journal of pharmacology
-
The behavioural noxious heat threshold i.e. the lowest temperature evoking nocifensive behaviour was previously shown to decrease in short-lasting, but not in sustained, inflammatory thermal hyperalgesias. The aim of this study was to examine whether the surgical incision-induced lasting heat hyperalgesia involves a drop of the heat threshold and to assess the effects of conventional opioid and non-opioid analgesics in this model. One of the hind paws of rats was immersed into a water bath whose temperature was near-linearly increased from 30 degrees C until the animal withdrew its paw from the water. ⋯ Thermal hyperalgesia was also decreased by intraplantar treatment with morphine (10 microg) or diclofenac (100 microg). In conclusion, the incision-induced sustained thermal hyperalgesia in rats involves a drop of the heat threshold suggesting that mechanisms of postsurgical pain are distinct from those of pure inflammatory pain. The thermal antihyperalgesic actions of systemically and/or locally applied morphine, diclofenac and paracetamol could be detected with high temporal resolution and sensitivity in this model.
-
To characterize the interactions between levetiracetam and the antiepileptic drugs gabapentin, tiagabine, and vigabatrin in suppressing pentylenetetrazole-induced clonic seizures in mice, type II isobolographic analysis was used. Clonic seizures were evoked in Albino Swiss mice by subcutaneous injection of pentylenetetrazole at its CD(97)(98 mg/kg). Adverse-effect profiles with respect to motor performance, long-term memory and skeletal muscular strength were measured along with total brain antiepileptic drug concentrations. ⋯ In contrast, levetiracetam was without affect on tiagabine or vigabatrin concentrations and co-administration with gabapentin, tiagabine or vigabatrin had no effect on levetiracetam brain concentrations, indicating the pharmacodynamic nature of interaction between these antiepileptic drugs in the mouse pentylenetetrazole model. The combination of gabapentin with levetiracetam at the fixed-ratios of 2:1, 1:1, 1:2, and 1:4 appears to be particularly favorable combination exerting supra-additive interaction in suppressing pentylenetetrazole-induced seizures, although there is a pharmacokinetic contribution to the interaction between levetiracetam and gabapentin at the fixed-ratio of 1:4. Levetiracetam in combination with tiagabine and vigabatrin appear to be neutral combinations producing only additivity in the mouse pentylenetetrazole model.
-
The formalin test is used as a primary behavioural screen for assaying the antinociceptive activity of compounds in laboratory rodents. After hindpaw formalin injection, nociceptive behaviours are expressed in a biphasic pattern and correlate closely with the concentration of formalin injected. Here, the antinociceptive efficacy of six compounds used in the clinical treatment of chronic pain was compared in rats injected with either 1% or 5% formalin. ⋯ However second phase nociception was only attenuated in 5% formalin-injected rats giving rise to a 6 fold increase in potency compared with 1% formalin-injected rats. The micro-opioid receptor agonist morphine (1-6 mg/kg) and the combined micro-opioid receptor agonist/monoamine reuptake inhibitor tramadol (5-50 mg/kg) both attenuated nociceptive behaviours throughout the duration of both the 1% and 5% tests; no difference in antinociceptive potency occurred for either compound during second phase. Thus, for mechanistically-distinct compounds the predictive antinociceptive capacity of the formalin test can vary with the concentration of formalin injected, likely as a result of peripheral and central nociceptive signalling mechanisms being differentially engaged.
-
A major symptom of persistent neuropathic pain, which may develop after peripheral nerve injury, is hypersensitivity (allodynia) to normally innocuous cold stimuli. Although the anticonvulsant pregabalin has been demonstrated to relieve neuropathic pain, both in preclinical models and clinically, the analgesic effect of the drug in animals has not been profiled for cold hypersensitivity. Therefore, we examined the effect of pregabalin (single oral dosing: 30, 100, 300 micromol/kg) on cold allodynia in two models of chronic neuropathic pain, the spared nerve injury (SNI) and the spinal nerve ligation (SNL) models. ⋯ For comparison, only the highest dose tested of pregabalin (300 micromol/kg), significantly decreased pain responses in phase 2 of the rat formalin test (approximately 67% pain inhibition). However, pregabalin at this high dose also affected other centrally mediated behavioural functions, such as motor activity and anxiolytic behaviour in naïve animals, which could potentially interfere with the pain readout. The present study demonstrates that oral administration of pregabalin significantly reduces both cold allodynia induced in the SNI and the SNL models of neuropathic pain as well as formalin-induced nociception, albeit with different sensitivity and potency.
-
Delta opioid receptor agonists are under development for a variety of clinical applications, and some findings in rats raise the possibility that agents with this mechanism have abuse liability. The present study assessed the effects of the non-peptidic delta opioid agonist SNC80 in an assay of intracranial self-stimulation (ICSS) in rats. ICSS was examined at multiple stimulation frequencies to permit generation of frequency-response rate curves and evaluation of curve shifts produced by experimental manipulations. ⋯ ICSS frequency-rate curves were also shifted by two non-pharmacological manipulations (reductions in stimulus intensity and increases in response requirement). Thus, SNC80 failed to facilitate or attenuate ICSS-maintained responding under conditions in which other pharmacological and non-pharmacological manipulations were effective. These results suggest that non-peptidic delta opioid receptor agonists have negligible abuse-related effects in rats.