An investigation into the underlying mechanisms of risperidone-induced antinociception through the cholinergic pathway.

Pain is a complex phenomenon involving the perception of physical discomfort caused by tissue damage in the body. Risperidone, a neuroleptic with dopamine (D2) and serotonin (5-HT2) receptor antagonistic potentials, also exhibits antinociceptive properties, however, its use in the treatment of peripheral nociception has received little attention. Hence, this study evaluated the antinociceptive effects of risperidone and its possible mechanism of action. Ninety Swiss mice (23-30 ​g) were divided into two phases: antinociceptive and mechanistic. Antinociceptive activity was assessed using acetic acid-induced writhing and formalin-induced paw-licking tests. In each model, mice were grouped (n ​= ​6) and treated with distilled water (control), risperidone (0.5, 1.0, and 1.5 ​mg/kg), or indomethacin (10 ​mg/kg). Mechanistic studies involved atropine, propranolol, or naloxone co-administered with risperidone (1.5 ​mg/kg). The results of the studies showed that risperidone significantly decreased neurogenic and inflammatory pain in the paw licking test while risperidone 1.5 ​mg/kg significantly decreased writhing in the acetic acid-induced writhing test. In the mechanistic studies, atropine co-administered with risperidone group showed significantly reversed anti-nociception when compared with risperidone 1.5 ​mg/kg alone in the paw-licking test model. Histological assessment of the mice paw tissues using Hematoxylin & Eosin, and Giemsa staining techniques revealed improved infiltration of inflammatory cells, which was significantly decreased in mice pre-treated with atropine, further supporting the analgesic potential of risperidone in the study. This study highlights risperidone's antinociceptive potential and suggests its mechanism is mediated via cholinergic pathways, offering insights into its therapeutic applications that can be implore in pain management.