Non-psychoactive cannabinoids modulate the descending pathway of antinociception in anaesthetized rats through several mechanisms of action

Authors

  • Sabatino Maione,

    1. Endocannabinoid Research Group, Department of Experimental Medicine – Division of Pharmacology ‘L. Donatelli’, Second University of Naples, Naples, Italy
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  • Fabiana Piscitelli,

    1. Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Pozzuoli (Naples), Italy
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  • Luisa Gatta,

    1. Endocannabinoid Research Group, Department of Experimental Medicine – Division of Pharmacology ‘L. Donatelli’, Second University of Naples, Naples, Italy
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  • Daniela Vita,

    1. Endocannabinoid Research Group, Department of Experimental Medicine – Division of Pharmacology ‘L. Donatelli’, Second University of Naples, Naples, Italy
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  • Luciano De Petrocellis,

    1. Endocannabinoid Research Group, Institute of Cybernetics, Consiglio Nazionale delle Ricerche, Pozzuoli (Naples), Italy
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  • Enza Palazzo,

    1. Endocannabinoid Research Group, Department of Experimental Medicine – Division of Pharmacology ‘L. Donatelli’, Second University of Naples, Naples, Italy
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  • Vito de Novellis,

    1. Endocannabinoid Research Group, Department of Experimental Medicine – Division of Pharmacology ‘L. Donatelli’, Second University of Naples, Naples, Italy
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  • Vincenzo Di Marzo

    Corresponding author
    1. Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Pozzuoli (Naples), Italy
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Vincenzo Di Marzo, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Via dei Campi Flegrei 34, 80078 Pozzuoli (Naples), Italy. E-mail: vdimarzo@icmib.na.cnr.it

Abstract

BACKGROUND AND PURPOSE

Two non-psychoactive cannabinoids, cannabidiol (CBD) and cannabichromene (CBC), are known to modulate in vitro the activity of proteins involved in nociceptive mechanisms, including transient receptor potential (TRP) channels of vanilloid type-1 (TRPV1) and of ankyrin type-1 (TRPA1), the equilibrative nucleoside transporter and proteins facilitating endocannabinoid inactivation. Here we have tested these two cannabinoids on the activity of the descending pathway of antinociception.

EXPERIMENTAL APPROACH

Electrical activity of ON and OFF neurons of the rostral ventromedial medulla in anaesthetized rats was recorded extracellularly and tail flick latencies to thermal stimuli were measured. CBD or CBC along with various antagonists were injected into the ventrolateral periaqueductal grey.

KEY RESULTS

Cannabidiol and CBC dose-dependently reduced the ongoing activity of ON and OFF neurons in anaesthetized rats, whilst inducing antinociceptive responses in the tail flick-test. These effects were maximal with 3 nmol CBD and 6 nmol CBC, and were antagonized by selective antagonists of cannabinoid CB1 adenosine A1 and TRPA1, but not of TRPV1, receptors. Both CBC and CBD also significantly elevated endocannabinoid levels in the ventrolateral periaqueductal grey. A specific agonist at TRPA1 channels and a synthetic inhibitor of endocannabinoid cellular reuptake exerted effects similar to those of CBC and CBD.

CONCLUSIONS AND IMPLICATIONS

CBD and CBC stimulated descending pathways of antinociception and caused analgesia by interacting with several target proteins involved in nociceptive control. These compounds might represent useful therapeutic agents with multiple mechanisms of action.

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