Neuropeptide VF Enhances Cannabinoid Agonist WIN55,212-2-Induced Antinociception in Mice.

Abstract

Cannabinoids produce analgesia in several pain models, but the undesirable side effects from high doses of cannabinoid drugs limit their clinic use. Our recent results indicate that cannabinoid-induced antinociception was enhanced by neuropeptide VF (NPVF). Here, we investigate whether low-dose cannabinoid agonists combined with NPVF can produce effective antinociception with limited side effects. The in vivo properties of (R)-(-1)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-napthalenylmethanone (WIN55,212-2) given alone and its combination with NPVF were evaluated in nociceptive modulation, locomotor activity, gastrointestinal transit, and tolerance development assays after intracerebroventricular administration in mice. In the radiant tail-flick test, the antinociception of combination of WIN55,212-2 and NPVF was more potent than that of cannabinoid agonist given alone, with an ED50 shift from 3.51 to 0.69 nmol; 9 nmol WIN55,212-2 alone and 3 nmol WIN55,212-2 combined with NPVF induced equivalent antinociception after supraspinal administration. The cannabinoid-potentiating effects of NPVF were reduced by both the cannabinoid receptor type 1 and the neuropeptide FF receptor antagonists. In the formalin assay, WIN55,212-2 combined with NPVF also significantly reduced pain-related behaviors. However, the combination of WIN55,212-2 with NPVF exerted significant hypoactivity in a manner similar to high doses of WIN55,212-2. It was important to note that the combination of WIN55,212-2 with NPVF produced nontolerance-forming antinociception and weaker inhibition of gastrointestinal transit compared with high dose of WIN55,212-2. These data suggest that the cannabinoid agonist combined with NPVF produces effective antinociception-lacking tolerance via both cannabinoid receptor type 1 and neuropeptide FF receptors in the brain.