Chaerophyllum macropodum Boiss. (popularly known as "Jafari farangi kohestani") is a predominantmedicinal planttraditionally utilized in the treatments ofperitoneal inflammation and headachein Persian folk medicine. Here, we have revealed the anti-neuropathic and anti-nociceptive activities of C. macropodum leaves essential oil (CMEO) in addition to uncovering the possible mechanisms of action. Formalin-induced paw licking model was used to assess the anti-nociceptive activity of CMEO and its major constituent, terpinolene (TP). The anti-nociceptive activity of these compounds was determined by investigating the roles of various non-opioid and NO-cGMP-K+ channels. Additionally, the anti-neuropathic potential of CMEO and TP was determined using cervical spinal cord contusion/CCS technique. The CMEO exerted significant anti-nociceptive activity with a remarkable activity seen in the second phase of formalin-induced paw licking model and this activity were remarkably reversed by pre-treatment of naloxone (an opioid antagonist). Pretreatment with several types of NO-cGMP-potassium channel pathway meaningfully reversed the anti-nociceptive potential of CMEO in phase II of formalin model. Moreover, pre-treatment with several antagonists of non-opioid receptors revealed that only the antagonist of TRPV-1, serotonin type 3, 5-HT2, α2 adrenergic, and CB1 receptors (capsaicin, ondansetron, ketanserin, yohimbine, and SR141716A, respectively) reversed CMEO anti-nociception. CMEO and TP also remarkably reversed hyperalgesia and mechanical allodynia in the CCS technique. The CMEO exerts anti-nociceptive and anti-neuropathic activities via the modulation of NO-cGMP potassium channel pathway, opioid as well as several non-opioid receptor activity. TP might partly contribute to the observed activities of CMEO.
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