Evidence for the presence of CB2-like cannabinoid receptors on peripheral nerve terminals

Griffin, Graeme; Fernando, Susanthi R.; Ross, Ruth A.; McKay, Neil G.; Ashford, M. L. J.; Shire, David; Huffman, John W.; Yu, Shu; Lainton, Julia A.H.; Pertwee, Roger G.

doi:10.1016/s0014-2999(97)01336-8

Cited by 160 publications

(113 citation statements)

References 20 publications

Supporting

Mentioning

104

Contrasting

Unclassified

Order By: Relevance

“…6), which was prevented by SR-144528, the CB 2 antagonist, but not by SR-141716A, the CB 1 antagonist. This observation is in agreement with reports on the presence of CB 2 -like receptors on peripheral nerve terminals (9,10), and with the report of Zimmer et al (43) on a residual analgesic effect of THC in CB 1 knockout mice. The Zimmer data indicate that THC may act in part through CB 2 , or a CB 2 -like receptor.…”

Section: Resultssupporting

confidence: 93%

HU-308: A specific agonist for CB ₂ , a peripheral cannabinoid receptor

Hanŭs

Breuer

Tchilibon

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

528

367

View full text Add to dashboard Cite

Two cannabinoid receptors have been identified: CB1, present in the central nervous system (CNS) and to a lesser extent in other tissues, and CB2, present outside the CNS, in peripheral organs. There is evidence for the presence of CB2-like receptors in peripheral nerve terminals. We report now that we have synthesized a CB2-specific agonist, code-named HU-308. This cannabinoid does not bind to CB1 (Ki > 10 M), but does so efficiently to CB2 (Ki ‫؍‬ 22.7 ؎ 3.9 nM); it inhibits forskolin-stimulated cyclic AMP production in CB2-transfected cells, but does so much less in CB1-transfected cells. HU-308 shows no activity in mice in a tetrad of behavioral tests, which together have been shown to be specific for tetrahydrocannabinol (THC)-type activity in the CNS mediated by CB1. However, HU-308 reduces blood pressure, blocks defecation, and elicits anti-inflammatory and peripheral analgesic activity. The hypotension, the inhibition of defecation, the anti-inflammatory and peripheral analgesic effects produced by HU-308 are blocked (or partially blocked) by the CB2 antagonist SR-144528, but not by the CB1 antagonist SR-141716A. These results demonstrate the feasibility of discovering novel nonpsychotropic cannabinoids that may lead to new therapies for hypertension, inflammation, and pain.

show abstract

Section: Resultssupporting

confidence: 93%

HU-308: A specific agonist for CB ₂ , a peripheral cannabinoid receptor

Hanŭs

Breuer

Tchilibon

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

528

367

View full text Add to dashboard Cite

show abstract

“…However, this action was not blocked by a selective CB 2 antagonist SR144528. Griffin et al (1997) reported that JWH-015 inhibited electrically evoked contractions in the mouse vas deferens and the guinea pig myenteric plexus and that this effect could be reversed by SR141716A in the myenteric plexus, suggesting that the inhibitory actions are CB 1 -mediated (Griffin et al, 1997). This is in agreement with our study in that the inhibitory actions of JWH-015 seemed to be attenuated in the presence of the CB 1 antagonist SR141716A.…”

Section: Discussionsupporting

confidence: 92%

Characterization of Cannabinoid Modulation of Sensory Neurotransmission in the Rat Isolated Mesenteric Arterial Bed

Duncan¹,

Kendall²,

Ralevic³

2004

J Pharmacol Exp Ther

View full text Add to dashboard Cite

The present study investigated the effects of different classes of cannabinoid (CB) receptor ligands on sensory neurotransmission in the rat isolated mesenteric arterial bed. Electrical field stimulation of the mesenteric bed evoked frequency-dependent vasorelaxation due to the activation of capsaicin-sensitive sensory nerves and release of calcitonin gene-related peptide (CGRP). The CB 1 /CB 2 cannabinoid agonists WIN55,212 The inhibitory actions of both THC and JWH-015 were still evident in the presence of SR141716A (1 M) and SR144528 (1 M). None of the cannabinoid agonists investigated had an effect on vasorelaxation elicited by exogenous CGRP, indicating a prejunctional mechanism. These data demonstrate that different classes of cannabinoid agonists attenuate sensory neurotransmission via a prejunctional site and provide evidence for mediation by a CB 1 and/or a non-CB 1 /CB 2 receptor.Two cannabinoid receptor subtypes, both G protein-linked, have been isolated and cloned to date; the CB 1 receptor is found mainly in the central nervous system and some peripheral nerve terminals, and the CB 2 receptor is associated mainly with immune tissues (Pertwee, 1999). There is evidence, however, that the cannabinoid receptor classification is incomplete. There are data that suggest the presence of multiple CB 1 subtypes in the spinal cord (Welch et al., 1998), and putative CB 2 -like receptors have been implicated in antinociceptive and hypotensive effects of cannabinoid agonists (Hanuš et al., 1999;Calignano et al., 2001). Experiments using CB receptor knockout mice have uncovered a putative novel cannabinoid receptor in the mouse brain (Di Marzo et al., 2000;Breivogel et al., 2001;Há jos et al., 2001;Monory et al., 2002). In addition, studies of the rat mesentery have described a novel anandamide-sensitive, SR141716A-sensitive endothelial receptor (Já rai et al., 1999). Recently, Zygmunt et al. (2002) reported that ⌬ 9 -tetrahydrocannabinol (THC) and cannabidiol induce a CB 1 /CB 2 -independent release of calcitonin gene-related peptide (CGRP) from capsaicin-sensitive nerves in isolated rat and mouse mesenteric arterial rings that could be blocked by the vanilloid receptor (TRPV1) blocker ruthenium red but that was still present in TRPV1 knockout animals.Capsaicin-sensitive sensory nerves are widely distributed in the cardiovascular system and have a dual function; an afferent function whereby they participate in reflex activation of motor nerves, and an efferent function, whereby neurotransmitter is released from the nerve terminal being stimulated (Maggi and Meli, 1988). Studies on dorsal root ganglia (DRG) and F-11 cells (DRG ϫ neuroblastoma hybridomas) indicate that both CB 1 and CB 2 receptor proteins exist in these cells (Ross et al., 2001). However, only CB 1 receptors have been demonstrated to be transported from DRG cell bodies to the periphery of the sensory nerves (Hohmann and Herkenham, 1999).Recently, functional evidence has been provided which This study was supported by Servier and the Univers...

show abstract

“…Thus CB2R has been demonstrated to reside on a wide variety of peripheral blood leukocytes and spleen cell populations (26) and to a greater extent than seen for CB1R in the same cell types that include B cells, T cells, NK cells, splenic macrophages, dendritic cells, and neutrophils (5,25,30). More recently, the existence of a CB2R on peripheral neurons (15) and perivascular microglial cells (37) in human brain has been reported.…”

Section: Discussionmentioning

confidence: 97%

Agonists of cannabinoid receptor 1 and 2 inhibit experimental colitis induced by oil of mustard and by dextran sulfate sodium

Kimball

Schneider²,

Wallace³

et al. 2006

American Journal of Physiology-Gastrointestinal and Liver Physi

161

168

View full text Add to dashboard Cite

of cannabinoid receptor 1 and 2 inhibit experimental colitis induced by oil of mustard and by dextran sulfate sodium. Am J Physiol Gastrointest Liver Physiol 291: G364 -G371, 2006. First published March 30, 2006 doi:10.1152/ajpgi.00407.2005.-Oil of mustard (OM) is a potent neuronal activator that is known to elicit visceral hyperalgesia when given intracolonically, but the full extent to which OM is also proinflammatory in the gastrointestinal tract is not known. We have previously shown that male CD-1 mice given a single administration of 0.5% OM develop a severe colitis that is maximum at day 3 and that gradually lessens until essentially absent by day 14. OM-induced neuronal stimulation is reported to be reduced by cannabinoid agonists, and cannabinoid receptor 1 (CB1R) Ϫ/Ϫ mice have exacerbated experimental colitis. Therefore, we examined the role of cannabinoids in this OM-induced 3-day model of colitis in CD-1 mice and in a 7-day dextran sulfate sodium (DSS) colitis model in BALB/c mice. In OM colitis, the CB1R-selective agonist ACEA and the CB2R-selective agonist JWH-133 reduced (P Ͻ 0.05) colon weight gain (means Ϯ SE; 82 Ϯ 13% and 47 Ϯ 15% inhibition, respectively), colon shrinkage (98 Ϯ 24% and 42 Ϯ 12%, respectively), colon inflammatory damage score (49 Ϯ 11% and 40 Ϯ 12%, respectively), and diarrhea (58 Ϯ 12% and 43 Ϯ 11%, respectively). Histological damage was similarly reduced by these treatments. Likewise, CBR agonists attenuated DSS colitis, albeit at higher doses; ACEA at 10 mg/kg, twice daily, inhibited (P Ͻ 0.05) macroscopic and microscopic scores (46 Ϯ 9% and 63 Ϯ 7%, respectively); whereas 20 mg/kg, twice daily, of JWH-133 was required to diminish (P Ͻ 0.05) macroscopic and microscopic scores (29 Ϯ 7% and 43 Ϯ 5%, respectively). CB1R and CB2R immunostaining of colon sections revealed that CB1R in enteric neurons was more intense in colitic vs. control mice; however, CB1R was also increased in the endothelial layer in OM colitis only. CB2R immunostaining was more marked in infiltrated immune cells in OM colitis. These findings validate the OM colitis model with respect to the DSS model and provide strong support to the emerging idea that cannabinoid receptor activation mediates protective mechanisms in experimental colitis. The demonstration of CB1R agonist effects in colitis support the neurogenic nature of the OM-induced colitis model and reinforce the importance of neuronal activation in intestinal inflammation.

show abstract

Evidence for the presence of CB2-like cannabinoid receptors on peripheral nerve terminals

Cited by 160 publications

References 20 publications

HU-308: A specific agonist for CB ₂ , a peripheral cannabinoid receptor

HU-308: A specific agonist for CB ₂ , a peripheral cannabinoid receptor

Characterization of Cannabinoid Modulation of Sensory Neurotransmission in the Rat Isolated Mesenteric Arterial Bed

Agonists of cannabinoid receptor 1 and 2 inhibit experimental colitis induced by oil of mustard and by dextran sulfate sodium

Contact Info

Product

Resources

About

Evidence for the presence of CB2-like cannabinoid receptors on peripheral nerve terminals

Cited by 160 publications

References 20 publications

HU-308: A specific agonist for CB 2 , a peripheral cannabinoid receptor

HU-308: A specific agonist for CB 2 , a peripheral cannabinoid receptor

Characterization of Cannabinoid Modulation of Sensory Neurotransmission in the Rat Isolated Mesenteric Arterial Bed

Agonists of cannabinoid receptor 1 and 2 inhibit experimental colitis induced by oil of mustard and by dextran sulfate sodium

Contact Info

Product

Resources

About

HU-308: A specific agonist for CB ₂ , a peripheral cannabinoid receptor

HU-308: A specific agonist for CB ₂ , a peripheral cannabinoid receptor