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. 2011 Feb;162(3):584-96.
doi: 10.1111/j.1476-5381.2010.01063.x.

Non-psychoactive Cannabinoids Modulate the Descending Pathway of Antinociception in Anaesthetized Rats Through Several Mechanisms of Action

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Free PMC article

Non-psychoactive Cannabinoids Modulate the Descending Pathway of Antinociception in Anaesthetized Rats Through Several Mechanisms of Action

Sabatino Maione et al. Br J Pharmacol. .
Free PMC article

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 CB(1) adenosine A(1) 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.

Figures

Figure 1
Figure 1
Chemical structures of cannabidiol (CBD) and cannabichromene (CBC).
Figure 2
Figure 2
Schematic illustration of the location of periaqueductal gray (PAG) microinjection sites (A) and rostral ventromedial medulla (RVM) ON or OFF cell recording sites (B). Vehicle or drug microinjections were performed in the ventrolateral (vl)-PAG (filled squares) (A). Open squares indicate the microinjection sites performed outside the vl-PAG, which were neither associated with change in RVM cell activity nor with tail-flick latency. Moreover, cell recordings performed by lowering a tungsten electrode into the RVM and ON cells (filled circles) or OFF cell (open circles) sites (B) are shown. Many sites are not shown to avoid symbol overlapping. Distances (mm) from the interaural line are indicated.
Figure 3
Figure 3
Effect of vehicle, cannabidiol (CBD) (1.5, 3 and 6 nmol) alone or CBD (3 nmol) in combination with AM251 (0.5 nmol), I-RTX (1 nmol), DPCPX (0.05 nmol), AP18 (6 nmol) or WAY100635 (0.34 nmol) on the spontaneous firing of rostral ventromedial medulla ON (A, C and E) or OFF (B, D and F) cells. A and B show the effect of intra-ventrolateral periaqueductal gray (vl-PAG) microinjections of vehicle and CBD (1.5, 3 and 6 nmol). C and D show the effect of intra-vl PAG administration of CBD (3 nmol) in combination with AM251 (0.5 nmol), I-RTX (1 nmol) or WAY100635 (0.34 nmol). E and F show the effect of intra-ventrolateral periaqueductal gray administration of CBD (3 nmol) in combination with DPCPX (0.05 nmol) or AP18 (6 nmol). Each point represents the mean ± standard error of the mean (SEM) of 6–8 neurons. Filled symbols indicate values significantly different (P < 0.05) from vehicle or CBD (3 nmol). DPCPX, 1,3-dipropyl-8-cyclopentylxanthine; I-RTX, 5′-iodo-resiniferatoxin.
Figure 4
Figure 4
Effects of intra-ventrolateral periaqueductal gray microinjections of vehicle, cannabidiol (CBD) (3 nmol), cannabichromene (CBC) (6 nmol), OMDM-2 (3 nmol) and mustard oil (6 mol) on the tail flick induced RVM ON burst of firing (A). B shows the effect of vehicle, CBD (3 nmol) alone or CBD (3 nmol) in combination with AM251 (0.5 nmol), I-RTX (1 nmol), DPCPX (0.05 nmol), AP18 (6 nmol) or WAY100635 (0.34 nmol). C shows the effect of vehicle, CBC (6 nmol) alone or CBC (6 nmol) in combination with AM251 (0.5 nmol), I-RTX (1 nmol), DPCPX (0.05 nmol) and AP18 (6 nmol). Each histogram represents the mean ± SEM of 6–8 neurons. * indicates values significantly different (P < 0.05) from vehicle and ° from CBD (3 nmol) or CBC (6 nmol). DPCPX, 1,3-dipropyl-8-cyclopentylxanthine; I-RTX, 5′-iodo-resiniferatoxin.
Figure 5
Figure 5
Effect of vehicle, cannabichromene (CBC) (3 and 6 nmol) alone or CBC (6 nmol) in combination with AM251 (0.5 nmol), I-RTX (1 nmol), DPCPX (0.05 nmol) and AP18 (6 nmol) on the spontaneous firing of RVM ON (A, C and E) or OFF (B, D and F) cells. A and B show the effect of intra-vl PAG microinjections of vehicle and CBC (3 and 6 nmol). C and D show the effect of intra-ventrolateral periaqueductal gray administration of CBC (6 nmol) in combination with AM251 (0.5 nmol) or I-RTX (1 nmol). E and F show the effect of intra-vl PAG administration of CBC (6 nmol) in combination with DPCPX (0.05 nmol) or AP18 (6 nmol). Each point represents the mean ± standard error of the mean (SEM) of 6–8 neurons. Filled symbols indicate values significantly different (P < 0.05) from vehicle and from CBC (6 nmol). DPCPX, 1,3-dipropyl-8-cyclopentylxanthine; I-RTX, 5′-iodo-resiniferatoxin; vl-PAG, ventrolateral periaqueductal grey.
Figure 6
Figure 6
Effect of vehicle, cannabidiol (CBD) (1.5, 3 and 6 nmol) and cannabichromene (CBC) (3 and 6 nmol) alone or CBD (3 nmol) or CBC (6 nmol) in combination with AM251 (0.5 nmol), I-RTX (1 nmol), DPCPX (0.05 nmol) and AP18 (6 nmol) on the tail-flick latency. A shows the effect of intra-vl PAG microinjections of vehicle and CBD (1.5, 3 and 6 nmol). B shows the effect of intra-vl PAG administration of CBC (3 and 6 nmol). C shows the effect of intra-vl PAG administration of CBD (3 nmol) in combination with AM251 (0.5 nmol), I-RTX (1 nmol) or WAY100635 (0.34 nmol). D shows the effect of intra-vl PAG administration of CBC (6 nmol) in combination with AM251 (0.5 nmol) or I-RTX (1 nmol). E shows the effect of intra-vl PAG administration of CBD (3 nmol) in combination with DPCPX (0.05 nmol) or AP18 (6 nmol). F shows the effect of intra-vl PAG administration of CBC (6 nmol) in combination with DPCPX (0.05 nmol) or AP18 (6 nmol). Each point represents the mean ± standard error of the mean (S.E.M) of 12–16 rats. Filled symbols indicate values significantly different (P < 0.05) from vehicle or from CBD (3 nmol) and CBC (6 nmol). DPCPX, 1,3-dipropyl-8-cyclopentylxanthine; I-RTX, 5′-iodo-resiniferatoxin; vl-PAG, ventrolateral periaqueductal grey.
Figure 7
Figure 7
Effect of vehicle, OMDM-2 (1.5 and 3 nmol) or mustard oil (3 and 6 nmol) on the spontaneous firing of rostral ventromedial medulla ON (A and C) and OFF (B and D) cells and on nocifensive behaviour through tail flick test (E and F). Each point represents the mean ± standard error of the mean (SEM) of 6–8 neurons (A and D) or 12–16 rats (E and F) per groups. Filled symbols indicate values significantly different (P < 0.05) from vehicle.

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