| Autor: |
Schwarz AM; Department of Pharmacology, College of Medicine, University of Arizona, Tucson AZ USA., Keresztes A; Department of Pharmacology, College of Medicine, University of Arizona, Tucson AZ USA., Bui T; Department of Pharmacology, College of Medicine, University of Arizona, Tucson AZ USA., Hecksel RJ; Department of Pharmacology, College of Medicine, University of Arizona, Tucson AZ USA., Peña A; Department of Pharmacology, College of Medicine, University of Arizona, Tucson AZ USA., Lent B; Department of Pharmacology, College of Medicine, University of Arizona, Tucson AZ USA., Gao ZG; Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda MD USA., Gamez-Rivera M; Department of Pharmacology, College of Medicine, University of Arizona, Tucson AZ USA., Seekins CA; Department of Pharmacology, College of Medicine, University of Arizona, Tucson AZ USA., Chou K; Department of Pharmacology, College of Medicine, University of Arizona, Tucson AZ USA., Appel TL; Department of Pharmacology, College of Medicine, University of Arizona, Tucson AZ USA., Jacobson KA; Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda MD USA., Al-Obeidi FA; Department of Pharmacology, College of Medicine, University of Arizona, Tucson AZ USA., Streicher JM; Department of Pharmacology, College of Medicine, University of Arizona, Tucson AZ USA.; Comprehensive Pain and Addiction Center, University of Arizona, Tucson AZ USA. |
| Abstrakt: |
Terpenes are small hydrocarbon compounds that impart aroma and taste to many plants, including Cannabis sativa . A number of studies have shown that terpenes can produce pain relief in various pain states in both humans and animals. However, these studies were methodologically limited and few established mechanisms of action. In our previous work, we showed that the terpenes geraniol, linalool, β-pinene, α-humulene, and β-caryophyllene produced cannabimimetic behavioral effects via multiple receptor targets. We thus expanded this work to explore the efficacy and mechanism of these Cannabis terpenes in relieving chronic pain. We first tested for antinociceptive efficacy by injecting terpenes (200 mg/kg, IP) into male and female CD-1 mice with chemotherapy-induced peripheral neuropathy (CIPN) or lipopolysaccharide-induced inflammatory pain, finding that the terpenes produced roughly equal efficacy to 10 mg/kg morphine or 3.2 mg/kg WIN55,212. We further found that none of the terpenes produced reward as measured by conditioned place preference, while low doses of terpene (100 mg/kg) combined with morphine (3.2 mg/kg) produced enhanced antinociception vs. either alone. We then used the adenosine A 2A receptor (A 2A R) selective antagonist istradefylline (3.2 mg/kg, IP) and spinal cord-specific CRISPR knockdown of the A 2A R to identify this receptor as the mechanism for terpene antinociception in CIPN. In vitro cAMP and binding studies and in silico modeling studies further suggested that the terpenes act as A 2A R agonists. Together these studies identify Cannabis terpenes as potential therapeutics for chronic neuropathic pain, and identify a receptor mechanism in the spinal cord for this activity. |
