Anti-neuropathic Pain Mechanistic Study on A. conyzoides Essential Oil, Precocene II, Caryophyllene, or Longifolene as Single Agents and in Combination with Pregabalin

Abstract

Background: Neuropathic pain has become a contributor to the global burden of illness. However, the currently available drugs exhibit inadequate pain relief and significant side effects. Our previous study demonstrated that the essential oil of Ageratum conyzoides exerts potent antineuropathic pain activity through opioid receptor activation. Precocene II, longifolene, and caryophyllene are the largest component of the A. conyzoides essential oil. Objective: The objective of the study was to determine the anti-neuropathic pain activity of precocene II, longifolene, and caryophyllene as single agents and in combination with pregabalin. Possible mechanisms of action involving the opioid receptor, ATP-sensitive potassium channel, and gammaaminobutyric acid (GABA) were further investigated. Methods: The experimental animals (male mice Swiss Webster) were divided randomly into seven groups, namely, Normal control (naïve mice), Negative control (CMC 1%), Sham (CMC 1%), Positive control (Pregabalin 0,195 mg/ 20 g BW of mice), Test I (Precocene II 21.09 mg/Kg BW), Test II (Longifolene 9.94 mg/Kg BW), and Test III (Caryophyllene 3.64 mg/Kg BW). Each group contained 3 animals. The test groups that demonstrated anti-neuropathic pain activity were further tested in combination with pregabalin, followed by mechanistic studies. The negative, positive, and test I-III groups were induced with chronic constriction injury. Results: The results of the study demonstrated that caryophyllene and longifolene, but not precocene II, exerted anti-neuropathic pain activity. The caryophyllene was shown to involve in the activation of opioid receptors and ATP-sensitive potassium channels. It was also reported to increase GABA concentration in the spinal cord. We further found that longifolene exerted its action via opioid receptor activation. The combination of A. conyzoides essential oil, longifolene, or caryophyllene with pregabalin demonstrated additive anti-neuropathic pain activity. Conclusion: Taken together, the results of the present study suggested that the A. conyzoides essential oil and caryophyllene have the potential to be developed as novel drugs to treat neuropathic pain.