Positive Allosteric Modulation of Cannabinoid Receptor Type 1 Suppresses Pathological Pain Without Producing Tolerance or Dependence

Richard A. Slivicki, Zhili Xu, Pushkar M. Kulkarni, Roger G. Pertwee, Ken Mackie, Ganesh A. Thakur, Andrea G. Hohmann

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Background: Activation of cannabinoid CB1 receptors suppresses pathological pain but also produces unwanted central side effects. We hypothesized that a positive allosteric modulator of CB1 signaling would suppress inflammatory and neuropathic pain without producing cannabimimetic effects or physical dependence. We also asked whether a CB1 positive allosteric modulator would synergize with inhibitors of endocannabinoid deactivation and/or an orthosteric cannabinoid agonist. Methods: GAT211, a novel CB1 positive allosteric modulator, was evaluated for antinociceptive efficacy and tolerance in models of neuropathic and/or inflammatory pain. Cardinal signs of direct CB1-receptor activation were evaluated together with the propensity to induce reward or aversion and physical dependence. Comparisons were made with inhibitors of endocannabinoid deactivation (JZL184, URB597) or an orthosteric cannabinoid agonist (WIN55,212-2). All studies used 4 to 11 subjects per group. Results: GAT211 suppressed allodynia induced by complete Freund's adjuvant and the chemotherapeutic agent paclitaxel in wild-type but not CB1 knockout mice. GAT211 did not impede paclitaxel-induced tumor cell line toxicity. GAT211 did not produce cardinal signs of direct CB1-receptor activation in the presence or absence of pathological pain. GAT211 produced synergistic antiallodynic effects with fatty acid amide hydrolase and monoacylglycerol lipase inhibitors in paclitaxel-treated mice. Therapeutic efficacy was preserved over 19 days of chronic dosing with GAT211, but it was not preserved with the monoacylglycerol lipase inhibitor JZL184. The CB1 antagonist rimonabant precipitated withdrawal in mice treated chronically with WIN55,212-2 but not in mice treated with GAT211. GAT211 did not induce conditioned place preference or aversion. Conclusions: Positive allosteric modulation of CB1-receptor signaling shows promise as a safe and effective analgesic strategy that lacks tolerance, dependence, and abuse liability.

Original languageEnglish
Pages (from-to)722-733
Number of pages12
JournalBiological Psychiatry
Volume84
Issue number10
Early online date8 Jul 2017
DOIs
Publication statusPublished - 15 Nov 2018

Fingerprint

Cannabinoid Receptor CB1
Cannabinoid Receptors
Monoacylglycerol Lipases
Paclitaxel
Cannabinoid Receptor Agonists
Pain
Endocannabinoids
rimonabant
Freund's Adjuvant
Hyperalgesia
Neuralgia
Tumor Cell Line
Reward
Knockout Mice
Analgesics
JZL 184
Therapeutics

Keywords

  • Allosteric modulator
  • Endocannabinoid
  • Neuropathic pain
  • Physical dependence
  • Reward
  • Withdrawal

ASJC Scopus subject areas

  • Biological Psychiatry

Cite this

Positive Allosteric Modulation of Cannabinoid Receptor Type 1 Suppresses Pathological Pain Without Producing Tolerance or Dependence. / Slivicki, Richard A.; Xu, Zhili; Kulkarni, Pushkar M.; Pertwee, Roger G.; Mackie, Ken; Thakur, Ganesh A.; Hohmann, Andrea G.

In: Biological Psychiatry, Vol. 84, No. 10, 15.11.2018, p. 722-733.

Research output: Contribution to journalArticle

Slivicki, Richard A. ; Xu, Zhili ; Kulkarni, Pushkar M. ; Pertwee, Roger G. ; Mackie, Ken ; Thakur, Ganesh A. ; Hohmann, Andrea G. / Positive Allosteric Modulation of Cannabinoid Receptor Type 1 Suppresses Pathological Pain Without Producing Tolerance or Dependence. In: Biological Psychiatry. 2018 ; Vol. 84, No. 10. pp. 722-733.
@article{907ba748afda4852be2704533cebc6f4,
title = "Positive Allosteric Modulation of Cannabinoid Receptor Type 1 Suppresses Pathological Pain Without Producing Tolerance or Dependence",
abstract = "Background: Activation of cannabinoid CB1 receptors suppresses pathological pain but also produces unwanted central side effects. We hypothesized that a positive allosteric modulator of CB1 signaling would suppress inflammatory and neuropathic pain without producing cannabimimetic effects or physical dependence. We also asked whether a CB1 positive allosteric modulator would synergize with inhibitors of endocannabinoid deactivation and/or an orthosteric cannabinoid agonist. Methods: GAT211, a novel CB1 positive allosteric modulator, was evaluated for antinociceptive efficacy and tolerance in models of neuropathic and/or inflammatory pain. Cardinal signs of direct CB1-receptor activation were evaluated together with the propensity to induce reward or aversion and physical dependence. Comparisons were made with inhibitors of endocannabinoid deactivation (JZL184, URB597) or an orthosteric cannabinoid agonist (WIN55,212-2). All studies used 4 to 11 subjects per group. Results: GAT211 suppressed allodynia induced by complete Freund's adjuvant and the chemotherapeutic agent paclitaxel in wild-type but not CB1 knockout mice. GAT211 did not impede paclitaxel-induced tumor cell line toxicity. GAT211 did not produce cardinal signs of direct CB1-receptor activation in the presence or absence of pathological pain. GAT211 produced synergistic antiallodynic effects with fatty acid amide hydrolase and monoacylglycerol lipase inhibitors in paclitaxel-treated mice. Therapeutic efficacy was preserved over 19 days of chronic dosing with GAT211, but it was not preserved with the monoacylglycerol lipase inhibitor JZL184. The CB1 antagonist rimonabant precipitated withdrawal in mice treated chronically with WIN55,212-2 but not in mice treated with GAT211. GAT211 did not induce conditioned place preference or aversion. Conclusions: Positive allosteric modulation of CB1-receptor signaling shows promise as a safe and effective analgesic strategy that lacks tolerance, dependence, and abuse liability.",
keywords = "Allosteric modulator, Endocannabinoid, Neuropathic pain, Physical dependence, Reward, Withdrawal",
author = "Slivicki, {Richard A.} and Zhili Xu and Kulkarni, {Pushkar M.} and Pertwee, {Roger G.} and Ken Mackie and Thakur, {Ganesh A.} and Hohmann, {Andrea G.}",
note = "Acknowledgments and Disclosures This work was supported by the National Institute of Drug Abuse Grant Nos. DA041229 (to AGH and KM), DA009158 (to KM and AGH), DA021696 (to KM), and T32DA024628 (to RAS); the National Cancer Institute Grant No. CA200417 (to AGH); and the National Eye Institute Grant No. EY024717 (to GAT). RAS is also supported by the 2017 Harlan Research Scholars program. We thank Ben Cornett for assistance with genotyping and Ben Cravatt for providing FAAH KO and MGL KO mice used to establish our breeding colony. The authors report no biomedical financial interests or potential conflicts of interest.",
year = "2018",
month = "11",
day = "15",
doi = "10.1016/j.biopsych.2017.06.032",
language = "English",
volume = "84",
pages = "722--733",
journal = "Biological Psychiatry",
issn = "0006-3223",
publisher = "Elsevier USA",
number = "10",

}

TY - JOUR

T1 - Positive Allosteric Modulation of Cannabinoid Receptor Type 1 Suppresses Pathological Pain Without Producing Tolerance or Dependence

AU - Slivicki, Richard A.

AU - Xu, Zhili

AU - Kulkarni, Pushkar M.

AU - Pertwee, Roger G.

AU - Mackie, Ken

AU - Thakur, Ganesh A.

AU - Hohmann, Andrea G.

N1 - Acknowledgments and Disclosures This work was supported by the National Institute of Drug Abuse Grant Nos. DA041229 (to AGH and KM), DA009158 (to KM and AGH), DA021696 (to KM), and T32DA024628 (to RAS); the National Cancer Institute Grant No. CA200417 (to AGH); and the National Eye Institute Grant No. EY024717 (to GAT). RAS is also supported by the 2017 Harlan Research Scholars program. We thank Ben Cornett for assistance with genotyping and Ben Cravatt for providing FAAH KO and MGL KO mice used to establish our breeding colony. The authors report no biomedical financial interests or potential conflicts of interest.

PY - 2018/11/15

Y1 - 2018/11/15

N2 - Background: Activation of cannabinoid CB1 receptors suppresses pathological pain but also produces unwanted central side effects. We hypothesized that a positive allosteric modulator of CB1 signaling would suppress inflammatory and neuropathic pain without producing cannabimimetic effects or physical dependence. We also asked whether a CB1 positive allosteric modulator would synergize with inhibitors of endocannabinoid deactivation and/or an orthosteric cannabinoid agonist. Methods: GAT211, a novel CB1 positive allosteric modulator, was evaluated for antinociceptive efficacy and tolerance in models of neuropathic and/or inflammatory pain. Cardinal signs of direct CB1-receptor activation were evaluated together with the propensity to induce reward or aversion and physical dependence. Comparisons were made with inhibitors of endocannabinoid deactivation (JZL184, URB597) or an orthosteric cannabinoid agonist (WIN55,212-2). All studies used 4 to 11 subjects per group. Results: GAT211 suppressed allodynia induced by complete Freund's adjuvant and the chemotherapeutic agent paclitaxel in wild-type but not CB1 knockout mice. GAT211 did not impede paclitaxel-induced tumor cell line toxicity. GAT211 did not produce cardinal signs of direct CB1-receptor activation in the presence or absence of pathological pain. GAT211 produced synergistic antiallodynic effects with fatty acid amide hydrolase and monoacylglycerol lipase inhibitors in paclitaxel-treated mice. Therapeutic efficacy was preserved over 19 days of chronic dosing with GAT211, but it was not preserved with the monoacylglycerol lipase inhibitor JZL184. The CB1 antagonist rimonabant precipitated withdrawal in mice treated chronically with WIN55,212-2 but not in mice treated with GAT211. GAT211 did not induce conditioned place preference or aversion. Conclusions: Positive allosteric modulation of CB1-receptor signaling shows promise as a safe and effective analgesic strategy that lacks tolerance, dependence, and abuse liability.

AB - Background: Activation of cannabinoid CB1 receptors suppresses pathological pain but also produces unwanted central side effects. We hypothesized that a positive allosteric modulator of CB1 signaling would suppress inflammatory and neuropathic pain without producing cannabimimetic effects or physical dependence. We also asked whether a CB1 positive allosteric modulator would synergize with inhibitors of endocannabinoid deactivation and/or an orthosteric cannabinoid agonist. Methods: GAT211, a novel CB1 positive allosteric modulator, was evaluated for antinociceptive efficacy and tolerance in models of neuropathic and/or inflammatory pain. Cardinal signs of direct CB1-receptor activation were evaluated together with the propensity to induce reward or aversion and physical dependence. Comparisons were made with inhibitors of endocannabinoid deactivation (JZL184, URB597) or an orthosteric cannabinoid agonist (WIN55,212-2). All studies used 4 to 11 subjects per group. Results: GAT211 suppressed allodynia induced by complete Freund's adjuvant and the chemotherapeutic agent paclitaxel in wild-type but not CB1 knockout mice. GAT211 did not impede paclitaxel-induced tumor cell line toxicity. GAT211 did not produce cardinal signs of direct CB1-receptor activation in the presence or absence of pathological pain. GAT211 produced synergistic antiallodynic effects with fatty acid amide hydrolase and monoacylglycerol lipase inhibitors in paclitaxel-treated mice. Therapeutic efficacy was preserved over 19 days of chronic dosing with GAT211, but it was not preserved with the monoacylglycerol lipase inhibitor JZL184. The CB1 antagonist rimonabant precipitated withdrawal in mice treated chronically with WIN55,212-2 but not in mice treated with GAT211. GAT211 did not induce conditioned place preference or aversion. Conclusions: Positive allosteric modulation of CB1-receptor signaling shows promise as a safe and effective analgesic strategy that lacks tolerance, dependence, and abuse liability.

KW - Allosteric modulator

KW - Endocannabinoid

KW - Neuropathic pain

KW - Physical dependence

KW - Reward

KW - Withdrawal

UR - http://www.scopus.com/inward/record.url?scp=85027451984&partnerID=8YFLogxK

U2 - 10.1016/j.biopsych.2017.06.032

DO - 10.1016/j.biopsych.2017.06.032

M3 - Article

VL - 84

SP - 722

EP - 733

JO - Biological Psychiatry

JF - Biological Psychiatry

SN - 0006-3223

IS - 10

ER -