Orofacial antinociceptive effects of perillyl alcohol associated with codeine and its possible modes of action

Abstract

This study evaluated the orofacial antinociceptive effect of (S)-(-)-perillyl alcohol (PA) associated with codeine (C) and investigated the possible molecular anchorage mechanisms of PA. Mice (n = 5 per group) were treated with PA alone and associated with codeine and assigned to the following groups: 75.0 mg/kg PA; 75.0 mg/kg PA + C 30 mg/kg; PA 37.5 mg/kg + C 15.0 mg/kg; C 30.0 mg/kg; and control. Nociception was induced by formalin, capsaicin, and glutamate, and was quantified based on the duration (in seconds) of face grooming. The possible mechanisms of action were evaluated by molecular docking study. In the formalin test, PA75/C30 presented an effect in the neurogenic (p < 0.0001) and inflammatory (p < 0.005) phases. Mice treated with PA75 (p < 0.0001) and PA75/C30 (p < 0.0005) showed a reduced nociceptive behavior in the capsaicin test. Glutamate-induced nociception also was blocked by PA75 (p < 0.0005) and C30 (p < 0.0005). The molecular anchorage analysis indicated high negative binding energy values for the evaluated receptors, especially glutamate receptors (AMPA -79.57 Kcal/mol, mGLUR6 -71.25, and NMDA -66.33 Kcal/mol). PA associated with codeine showed orofacial antinociceptive activity, with theoretical evidence of interaction with glutamate receptors.

Exogenous histamine and H2 receptor activation and H3 receptor inhibition in nucleus accumbens modulate formalin-induced orofacial nociception through opioid receptors

“…The orofacial formalin test is one of the most common animal models for studying nociception in the trigeminal region, and are included a first brief phase, which is associated with the chemogenic stimulation of nociceptors, and an extended second phase, caused by integration between nociceptors and spinal and brainstem signaling (Raboisson and Dallel, 2004). Thus, our results support previous findings, which showed a typical biphasic pattern of face rubbing behavior for orofacial formalin nociception model (Clavelou et al ., 1995; Raboisson and Dallel, 2004; Tamaddonfard et al ., 2011; Sugimoto et al ., 2021; Limeira et al ., 2022). Moreover, because the phases of the estrous cycle of female rats could alter the response of animals to nociception (Bradshaw et al ., 2000; Hurley and Adams, 2008), we conducted this experiment only on the male rats.…”