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Cannabinoid-induced lower lip retraction in rats

  • Girish R. Chopda
  • Spyros P. Nikas
  • Rishi Sharma
  • Shashank Kulkarni
  • Alexandros Makriyannis
  • Carol A. ParonisEmail author
Original Investigation

Abstract

Rationale

Lower lip retraction (LLR) in rats has been described as a distinctive effect of 5-HT1A agonists. In the course of evaluating behavioral effects of cannabinoid agonists in rats, LLR effects were evident following injection of several cannabinoid agonists.

Objectives

To pharmacologically characterize cannabinoid-induced LLR in rats.

Methods

Lower lip retraction was scored using a 3-point scale for up to 6 h after injection of the cannabinoid agonists Δ9-tetrahydrocannabinol (Δ9-THC, 1–10 mg/kg), AM7499 (0.01–1.0 mg/kg), or AM2389 (0.003–0.1 mg/kg), or, for comparison, the 5-HT1A agonist 8-OH-DPAT (0.01–0.3 mg/kg). Next, antagonist effects of rimonabant (1–10 mg/kg) and WAY100635 (0.3 mg/kg) on LLR produced by cannabinoid or 5-HT1A agonists were evaluated. Lastly, effects of 8-OH-DPAT were determined following pretreatment with AM2389 (0.003–0.01 mg/kg) or Δ9-THC (1 mg/kg).

Results

All three cannabinoid agonists produced LLR. Effects of AM2389 were attenuated by both rimonabant and WAY100635 whereas effects of 8-OH-DPAT were antagonized by WAY 100635 but not by rimonabant. Pretreatment with 1 mg/kg Δ9-THC or 0.01 mg/kg AM2389 shifted the 8-OH-DPAT dose-effect function for LLR to the left and isobolographic analysis of the data indicates CB1 and 5-HT1A interactions can be supraadditive.

Conclusions

Cannabinoid agonists produce LLR in rats, an effect heretofore ascribed only to activity at 5-HT1A receptors, via CB1 receptor-mediated actions. Co-administration of a cannabinoid agonist and the 5-HT1A agonist 8-OH-DPAT results in a synergistic effect on LLR.

Keywords

Lower lip retraction Cannabinoid Δ9-THC AM2389 AM7499 8-OH-DPAT 

Notes

Acknowledgments

The authors thank Roger Spealman, Jack Bergman, Brian Kangas, and Fernando de Moura for comments on a previous version of the manuscript.

Funding information

This work was supported by the National Institutes of Health [Grants DA023142, DA043700].

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Girish R. Chopda
    • 1
    • 2
  • Spyros P. Nikas
    • 1
  • Rishi Sharma
    • 1
    • 3
  • Shashank Kulkarni
    • 1
    • 4
  • Alexandros Makriyannis
    • 1
  • Carol A. Paronis
    • 1
    • 5
    Email author
  1. 1.Center for Drug Discovery, Department of Pharmaceutical SciencesNortheastern UniversityBostonUSA
  2. 2.Preclinical DevelopmentDicerna PharmaceuticalsCambridgeUSA
  3. 3.Charles River LaboratoriesSan FranciscoUSA
  4. 4.EMD Serono R&D InstituteBillericaUSA
  5. 5.Preclinical PharmacologyMcLean HospitalBelmontUSA

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