Liting Deng1, Josée Guindon2, Benjamin L Cornett3, Alexandros Makriyannis4, Ken Mackie5, Andrea G Hohmann6. 1. Program in Neuroscience, Indiana University, Bloomington, Indiana; Department of Molecular and Cellular Biochemistry, Indiana University, Bloomington, Indiana; Interdisciplinary Biochemistry Graduate Program, Indiana University, Bloomington, Indiana. 2. Program in Neuroscience, Indiana University, Bloomington, Indiana; Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana. 3. Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana. 4. Center for Drug Discovery, Bouvé College of Health Sciences, Northeastern University, Boston, Massachusetts. 5. Program in Neuroscience, Indiana University, Bloomington, Indiana; Interdisciplinary Biochemistry Graduate Program, Indiana University, Bloomington, Indiana; Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana. 6. Program in Neuroscience, Indiana University, Bloomington, Indiana; Interdisciplinary Biochemistry Graduate Program, Indiana University, Bloomington, Indiana; Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana. Electronic address: hohmanna@indiana.edu.
Abstract
BACKGROUND: Mixed cannabinoid receptor 1 and 2 (CB1 and CB2) agonists such as Δ(9)-tetrahydrocannabinol (Δ(9)-THC) can produce tolerance, physical withdrawal, and unwanted CB1-mediated central nervous system side effects. Whether repeated systemic administration of a CB2-preferring agonist engages CB1 receptors or produces CB1-mediated side effects is unknown. METHODS: We evaluated antiallodynic efficacy, possible tolerance, and cannabimimetic side effects of repeated dosing with a CB2-preferring agonist AM1710 in a model of chemotherapy-induced neuropathy produced by paclitaxel using CB1 knockout (CB1KO), CB2 knockout (CB2KO), and wild-type (WT) mice. Comparisons were made with the prototypic classic cannabinoid Δ(9)-THC. We also explored the site and possible mechanism of action of AM1710. RESULTS: Paclitaxel-induced mechanical and cold allodynia developed to an equivalent degree in CB1KO, CB2KO, and WT mice. Both AM1710 and Δ(9)-THC suppressed established paclitaxel-induced allodynia in WT mice. In contrast to Δ(9)-THC, chronic administration of AM1710 did not engage CB1 activity or produce antinociceptive tolerance, CB1-mediated cannabinoid withdrawal, hypothermia, or motor dysfunction. Antiallodynic efficacy of systemic administration of AM1710 was absent in CB2KO mice and WT mice receiving the CB2 antagonist AM630, administered either systemically or intrathecally. Intrathecal administration of AM1710 also attenuated paclitaxel-induced allodynia in WT mice, but not CB2KO mice, implicating a possible role for spinal CB2 receptors in AM1710 antiallodynic efficacy. Finally, both acute and chronic administration of AM1710 decreased messenger RNA levels of tumor necrosis factor-α and monocyte chemoattractant protein 1 in lumbar spinal cord of paclitaxel-treated WT mice. CONCLUSIONS: Our results highlight the potential of prolonged use of CB2 agonists for managing chemotherapy-induced allodynia with a favorable therapeutic ratio marked by sustained efficacy and absence of tolerance, physical withdrawal, or CB1-mediated side effects.
BACKGROUND: Mixed cannabinoid receptor 1 and 2 (CB1 and CB2) agonists such as Δ(9)-tetrahydrocannabinol (Δ(9)-THC) can produce tolerance, physical withdrawal, and unwanted CB1-mediated central nervous system side effects. Whether repeated systemic administration of a CB2-preferring agonist engages CB1 receptors or produces CB1-mediated side effects is unknown. METHODS: We evaluated antiallodynic efficacy, possible tolerance, and cannabimimetic side effects of repeated dosing with a CB2-preferring agonist AM1710 in a model of chemotherapy-induced neuropathy produced by paclitaxel using CB1 knockout (CB1KO), CB2 knockout (CB2KO), and wild-type (WT) mice. Comparisons were made with the prototypic classic cannabinoid Δ(9)-THC. We also explored the site and possible mechanism of action of AM1710. RESULTS:Paclitaxel-induced mechanical and cold allodynia developed to an equivalent degree in CB1KO, CB2KO, and WT mice. Both AM1710 and Δ(9)-THC suppressed established paclitaxel-induced allodynia in WT mice. In contrast to Δ(9)-THC, chronic administration of AM1710 did not engage CB1 activity or produce antinociceptive tolerance, CB1-mediated cannabinoid withdrawal, hypothermia, or motor dysfunction. Antiallodynic efficacy of systemic administration of AM1710 was absent in CB2KO mice and WT mice receiving the CB2 antagonist AM630, administered either systemically or intrathecally. Intrathecal administration of AM1710 also attenuated paclitaxel-induced allodynia in WT mice, but not CB2KO mice, implicating a possible role for spinal CB2 receptors in AM1710 antiallodynic efficacy. Finally, both acute and chronic administration of AM1710 decreased messenger RNA levels of tumor necrosis factor-α and monocyte chemoattractant protein 1 in lumbar spinal cord of paclitaxel-treated WT mice. CONCLUSIONS: Our results highlight the potential of prolonged use of CB2 agonists for managing chemotherapy-induced allodynia with a favorable therapeutic ratio marked by sustained efficacy and absence of tolerance, physical withdrawal, or CB1-mediated side effects.
Authors: Elizabeth J Rahn; Alexander M Zvonok; Ganesh A Thakur; Atmaram D Khanolkar; Alexandros Makriyannis; Andrea G Hohmann Journal: J Pharmacol Exp Ther Date: 2008-07-29 Impact factor: 4.030
Authors: Robson da Costa; Giselle F Passos; Nara L M Quintão; Elizabeth S Fernandes; João Raphael L C B Maia; Maria Martha Campos; João B Calixto Journal: Br J Pharmacol Date: 2020-06-03 Impact factor: 8.739
Authors: Ai-Ling Li; Xiaoyan Lin; Amey S Dhopeshwarkar; Ana Carla Thomaz; Lawrence M Carey; Yingpeng Liu; Spyros P Nikas; Alexandros Makriyannis; Ken Mackie; Andrea G Hohmann Journal: Mol Pharmacol Date: 2018-11-30 Impact factor: 4.436
Authors: Richard A Slivicki; Shahin A Saberi; Vishakh Iyer; V Kiran Vemuri; Alexandros Makriyannis; Andrea G Hohmann Journal: J Pharmacol Exp Ther Date: 2018-10-01 Impact factor: 4.030
Authors: Zachary A Curry; Jenny L Wilkerson; Deniz Bagdas; S Lauren Kyte; Nipa Patel; Giulia Donvito; Mohammed A Mustafa; Justin L Poklis; Micah J Niphakis; Ku-Lung Hsu; Benjamin F Cravatt; David A Gewirtz; M Imad Damaj; Aron H Lichtman Journal: J Pharmacol Exp Ther Date: 2018-03-14 Impact factor: 4.030