Chronic cannabinoid receptor 2 activation reverses paclitaxel neuropathy without tolerance or cannabinoid receptor 1-dependent withdrawal.
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.
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.
Liting
L
Deng
Program in Neuroscience, Indiana University, Bloomington, Indiana; Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana.
Josée
J
Guindon
Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana.
Benjamin L
BL
Cornett
Center for Drug Discovery, Bouvé College of Health Sciences, Northeastern University, Boston, Massachusetts.
Alexandros
A
Makriyannis
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.
Ken
K
Mackie
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.
Andrea G
AG
Hohmann
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000633:toxicity*; D063386:Cannabinoid Receptor Agonists / Q000494:pharmacology; D063387:Cannabinoid Receptor Antagonists / Q000494:pharmacology; D018932:Chemokine CCL2 / Q000378:metabolism; D002867:Chromones / Q000494:pharmacology; D004195:Disease Models, Animal; D013759:Dronabinol / Q000494:pharmacology; D005260:Female; D006930:Hyperalgesia / Q000139:chemically induced* / Q000188:drug therapy* / Q000503:physiopathology; D007211:Indoles / Q000494:pharmacology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017239:Paclitaxel / Q000633:toxicity*; D012333:RNA, Messenger / Q000378:metabolism; D011897:Random Allocation; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D013116:Spinal Cord / Q000187:drug effects / Q000503:physiopathology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
C500321:3-(1,1-dimethyl-heptyl)-1-hydroxy-9-methoxy-benzo(c)chromen-6-one; D000972:Antineoplastic Agents, Phytogenic; D063386:Cannabinoid Receptor Agonists; D063387:Cannabinoid Receptor Antagonists; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D002867:Chromones; D007211:Indoles; D012333:RNA, Messenger; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D014409:Tumor Necrosis Factor-alpha; D013759:Dronabinol; D017239:Paclitaxel; C094023:iodopravadoline
CB(2); Chemotherapy-induced neuropathic pain; Knockout mouse; Precipitated withdrawal; Side effect; Tolerance