Pharmacological characterization of the chronic constriction injury model of neuropathic pain.

The chronic constriction injury model is a rat model of neuropathic pain based on a unilateral loose ligation of the sciatic nerve. The aim of the present study was to test its sensitivity to various clinically validated and experimental drugs. Mechanical allodynia and thermal hyperalgesia developed within one week post-surgery and were reliably present for at least 7 weeks. Mechanical allodynia was strongly attenuated by morphine (minimal effective dose in brackets: 8 mg/kg, p.o.) and the cannabinoids Delta9-tetrahydrocannabinol (3 mg/kg, p.o.) and (-)-cis-3-[2-hydroxy-4(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl) cyclohexanol (CP 55,940; 0.05 mg/kg, i.p.), and weakly/moderately attenuated by the anticonvulsants gabapentin (50 mg/kg, i.p.) and carbamazepine (32 mg/kg, i.p.), the muscle relaxant baclofen (3 mg/kg, i.p.), and the adenosine kinase inhibitor 4-amino-5-(3-bromophenyl)-7-(6-morpholino-pyridin-3-yl)pyrido[2,3-d]pyrimidine (ABT-702; 30 mg/kg, i.p.). Thermal hyperalgesia was strongly attenuated by morphine (16 mg/kg, p.o.), Delta9-tetrahydrocannabinol (6 mg/kg, p.o.), CP 55,940 (0.025 mg/kg, i.p.), carbamazepine (32 mg/kg, i.p.) and the antidepressant amitriptyline (32 mg/kg, p.o.), and weakly/moderately attenuated by gabapentin (50 mg/kg, i.p.), the anti-inflammatory cyclooxygenase-2 inhibitor rofecoxib (30 mg/kg, i.p.) and the adenosine A1 receptor positive allosteric modulator 2-amino-4,5,6,7-tetrahydrobenzo(b)thiophen-3-yl 4-chlorophenylmethanone (T62; 30 mg/kg, i.p.). Both symptoms were hardly or not affected by the nonselective N-methyl-d-aspartate receptor antagonists ketamine and dizocilpine, and the N-methyl-d-aspartate receptor NR2B-selective antagonists ifenprodil and R-(R*,S*)-alpha-(4-hydroxyphenyl)-beta-methyl-4-(phenyl-methyl)-1-piperidine propranol (Ro 25-6981). The finding that mechanical allodynia and/or thermal hyperalgesia are attenuated by various established compounds further supports the validity of the chronic constriction injury model for the study of neuropathic pain and its use for the identification of novel treatments.

Behavioral mechanisms underlying inhibition of food-maintained responding by the cannabinoid receptor antagonist/inverse agonist SR141716A.

This study investigated the possible behavioral mechanisms underlying the anorectic effect of the cannabinoid CB(1) receptor antagonist/inverse agonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride (SR141716A). Male or female rats were food-restricted and trained to emit stable responding in daily 10-min, fixed ratio 10 food-reinforced operant sessions. Under these conditions, as well as under free-feeding conditions, SR141716A inhibited food-maintained responding (ED(50) values ranging from 0.92 to 2.52 mg/kg, i.p.). In the same operant procedure, SR141716A suppressed intracranial self-stimulation with a potency which was slightly lower than the anorectic potency (ED(50): 4.50 mg/kg). As assessed during a 10-min test period SR141716A (1-10 mg/kg) did not affect activity counts; suggesting that the observed inhibition of operant behavior is not a direct consequence of impairment of locomotor activity. SR141716A, however, attenuated saccharin-preference in a conditioned taste aversion paradigm (ED(50): 6.45 mg/kg). Although the data support the suggestion that the anorectic effect of SR141716A results from an attenuating effect on the rewarding effect of food, the contribution of drug-induced aversion/malaise cannot be excluded.