ReviewCannabinoid modulation of peripheral autonomic and sensory neurotransmission
Introduction
Cannabinoids are a family of cell membrane-derived signalling molecules that are released from nerves, blood cells and endothelial cells, and have diverse biological effects, including actions on the immune, cardiovascular, and central and peripheral nervous systems. They act at two distinct types of G-protein-coupled receptors, cannabinoid CB1 and CB2 receptors Pertwee, 1993, Pertwee, 1997, Pertwee, 1999. Cannabinoid CB1 receptors are highly localised in the central nervous system and are also found in some peripheral tissues. Cannabinoid CB2 receptors are found outside the central nervous system, in particular in association with immune tissues. There is emerging evidence, however, that current cannabinoid receptor classification may be incomplete with the identification of non-CB1 non-CB2 cannabinoid-induced responses in a variety of tissues Járai et al., 1999, Wagner et al., 1999, Kunos and Batkai, 2001, White et al., 2001, Zygmunt et al., 2002. Further complexity was added with the discovery that the archetypal “endocannabinoid”, anandamide (Devane et al., 1992), is an agonist at the vanilloid VR1 receptor Zygmunt et al., 1999, Smart et al., 2000 which is highly expressed on sensory nerves. More recently, N-arachidonoyl-dopamine, a compound originally synthesised as an agonist selective for cannabinoid CB1 over CB2 receptors (Ki values 0.25 and 12 μM, respectively) (Bisogno et al., 2000), was found to be a naturally occurring capsaicin-like substance (“endovanilloid”) with potent activity at vanilloid VR1 receptors (Huang et al., 2002). Both anandamide and N-arachidonoyl-dopamine are structurally similar to capsaicin (Fig. 1), the archetypal vanilloid, raising important questions about nomenclature as these compounds are arguably members of the same family of signalling molecules.
Much of the interest in cannabinoids has focussed on their actions in the central nervous system, which is appropriate since their pronounced psychoactive effects have been known for centuries through the medicinal and recreational use of the cannabis plant Cannabis sativa (Butrica, 2002). The main psychoactive compound in the cannabis plant, Δ9-tetrahydrocannabinol (Fig. 2), was isolated by Gaoni and Mechoulam (1964). There is now growing evidence that cannabinoids can also modulate pre- and postjunctionally neurotransmission in the periphery. There is substantial evidence for a role of the cannabinoid CB1 receptor in inhibitory modulation of peripheral sympathetic, parasympathetic, enteric and sensory neurotransmitter release, and preliminary evidence for an involvement of non-CB1 non-CB2 cannabinoid-like receptors. The role of cannabinoid receptor ligands in modulation of sensory neurotransmission is complex, as certain of these (anandamide and N-arachidonoyl-dopamine to date) also activate vanilloid VR1 receptors (coexpressed with cannabinoid CB1 receptors), which excites sensory nerves and causes a release of sensory neurotransmitter. A number of recent reviews have considered the synthesis, uptake and enzymatic degradation of endocannabinoids, and the structure and properties of the various cannabinoid receptor agonists and antagonists now available Pertwee, 1997, Di Marzo et al., 1998, Mechoulam et al., 1998, Giuffrida et al., 2001, Howlett et al., 2002. The present review discusses the roles of cannabinoids as prejunctional modulators of peripheral autonomic and sensory neurotransmission.
Section snippets
Neuroeffector junction
Autonomic nerves have extensive varicose regions (1–2 μm diameter) free of Schwann cell envelopments separated by narrow (0.1–0.3 μm diameter) intervaricose regions (Burnstock, 1986). The varicose regions contain vesicles (which concentrate at the region of close apposition with the target cell) and mitochondria, and are the sites of neurotransmitter release. The prejunctional varicosity membranes are sometimes thickened, but there are rarely postjunctional specialisations, thus differing from
Sympathetic nerves
There is molecular evidence for the expression of cannabinoid receptors in sympathetic nerves. Cannabinoid CB1 receptor, but not CB2 receptor, mRNA is expressed in embryonic and adult sympathetic ganglia Ishac et al., 1996, Buckley et al., 1998. Cannabinoid CB1 and CB2-like receptor mRNA was detected in mouse vas deferens, a tissue richly innervated with sympathetic nerves (Griffin et al., 1997).
Direct evidence for the existence of prejunctional cannabinoid CB1 receptors on sympathetic nerves
Parasympathetic nerves
Cannabinoid CB1 receptor, but not CB2 receptor, mRNA is expressed in embryonic parasympathetic ganglia (Buckley et al., 1998).
In guinea-pig trachea, CP 55,940 inhibited electrically evoked acetylcholine release from parasympathetic nerves in an SR141716A-insensitive manner, but paradoxically had no effect on cholinergic contractile responses evoked by electrical field stimulation (Spicuzza et al., 2000). This underlines the fact that caution must be used in drawing conclusions about the
Enteric neurones/gastrointestinal tract
The role of cannabinoids in the gastrointestinal tract has recently been comprehensively reviewed (Pertwee, 2001a) and an overview only is presented here.
In guinea-pig myenteric plexus-longitudinal muscle, direct evidence of a prejunctional action of cannabinoids via cannabinoid CB1 receptors was provided with the demonstration that WIN 55,212 and CP 55,940 inhibited electrically evoked acetylcholine release, and this effect was blocked by SR141716A Pertwee et al., 1996a, Coutts and Pertwee,
Sensory nerves
The effects of cannabinoids on the peripheral efferent (motor) function of sensory nerves are discussed in this section. The roles of cannabinoid and vanilloid receptors in nociception have been recently reviewed and will not be considered further here Walker et al., 1999, Walker et al., 2002, Fuentes et al., 1999, Elphick and Egertová, 2001, Pertwee, 2001b, Di Marzo et al., 2002, Hohmann, 2002. It is noteworthy that changes in the function of the sensory nervous system can influence the
Whole animals
Cannabinoids elicit complex cardiovascular effects in whole animals, including both an increase and decrease in blood pressure and heart rate, which may be the result of actions at multiple sites (pre- and postjunctional), different species, and state of consciousness.
Niederhoffer and Szabo, 1999, Niederhoffer and Szabo, 2000 carried out a comprehensive series of experiments in pithed and conscious rabbits and identified a number of sites at which WIN 55,212-2 can modulate cardiovascular
Mechanism(s) of cannabinoid inhibition of neurotransmission via cannabinoid receptors
Cannabinoids can modulate neurotransmission via inhibition of neurotransmitter release at prejunctional sites and by postjunctional actions (e.g. functional antagonism caused by endothelium-dependent and -independent smooth muscle relaxation, and inhibition of the release of intracellular Ca2+ available for contraction). Mechanisms involved in cannabinoid smooth muscle relaxation have been recently reviewed (Randall et al., 2002) and only prejunctional mechanisms by which cannabinoids modulate
Mechanism of cannabinoid activation of sensory neurotransmission via vanilloid VR1 receptors
The mechanism by which anandamide activates vanilloid VR1 receptors remains unclear. The activation involves binding of the ligand to the receptor, as [3H]anandamide has been shown to bind to vanilloid VR1 receptors in membranes prepared from cells expressing recombinant vanilloid VR1 receptors (Olah et al., 2001). Furthermore, anandamide displaces [3H]resiniferatoxin from vanilloid VR1 receptor-expressing cells DePetrocellis et al., 2001, Ross et al., 2001b. This appears to be to an
Significance of cannabinoid activation of cannabinoid and vanilloid VR1 receptors
Activation of cannabinoid receptors on sympathetic, parasympathetic and myenteric nerves leads to an inhibition of neurotransmitter release and a decrease in associated motor functions. The role of cannabinoids in modulation of sensory neurotransmission is more complex as this may involve both inhibitory actions via cannabinoid receptors and excitatory actions via vanilloid VR1 receptors (Fig. 7). The biological significance of this is unclear, but a number of possibilities exist.
Cannabinoid CB1
Acknowledgments
V.R. is a Royal Society University Research Fellow. I am grateful to Dr. M.D. Randall for comments on the manuscript.
References (174)
- et al.
Cannabinoid receptors are expressed in nociceptive primary sensory neurons
Neuroscience
(2000) - et al.
The endogenous cannabinoid anandamide activates vanilloid receptors in the rat hippocampal slice
Neuropharmacology
(2001) - et al.
Anandamide transport inhibition by the vanilloid agonist olvanil
Eur. J. Pharmacol.
(1999) - et al.
A selective inverse agonist for central cannabinoid receptors inhibits mitogen-activated protein kinase activation stimulated by insulin or insulin-like growth factor: 1. Evidence for a new model of receptor/ligand interactions
J. Biol. Chem.
(1997) - et al.
The activity of anandamide at vanilloid VR1 receptors requires facilitated transport across the cell membrane and is limited by intracellular metabolism
J. Biol. Chem.
(2001) Biosynthesis and inactivation of endocannabinoids: relevance to their proposed role as neuromodulators
Life Sci.
(1999)- et al.
Endocannabinoids: endogenous cannabinoid receptor ligands with neuromodulatory action
Trends Neurosci.
(1998) - et al.
Endovanilloid signaling in pain
Curr. Opin. Neurobiol.
(2002) - et al.
Endothelin-1 affects capsaicin-evoked release of neuropeptides from rat vas deferens
Eur. J. Pharmacol.
(1999) - et al.
Cannabinoids as potential new analgesics
Life Sci.
(1999)
Evidence for the presence of CB2-like cannabinoid receptors on peripheral nerve terminals
Eur. J. Pharmacol.
Neuronal responses to cannabinoid receptor ligands in the solitary tract nucleus
Eur. J. Pharmacol.
Transmission by post-ganglionic axons of the autonomic nervous system: the importance of the specialized neuroeffector junction
Neuroscience
Spinal and peripheral mechanisms of cannabinoid antinociception: behavioural, neurophysiological and neuroanatomical perspectives
Chem. Phys. Lipids
Localization of central cannabinoid CB1 receptor messenger RNA in neuronal subpopulations of rat dorsal root ganglia: a double-label in situ hybridization study
Neuroscience
Cannabinoid receptors undergo axonal flow in sensory nerves
Neuroscience
The gastrointestinal pharmacology of cannabinoids
Curr. Opin. Pharmacol.
Pulmonary and systemic hemodynamic effects of Δ9-tetrahydrocannabinol in conscious and morphine-chloralose-anesthetised dogs: anesthetic influence on drug action
Eur. J. Pharmacol.
Retrograde signaling by endocannabinoids
Curr. Opin. Neurobiol.
SR141716A is an inverse agonist at the human cannabinoid CB1 receptor
Eur. J. Pharmacol.
Pharmacological characterisation of cannabinoid CB1 receptors in the rat and mouse
Eur. J. Pharmacol.
Anandamide induces apoptosis in human cells via vanilloid receptors—evidence for a protective role of cannabinoid receptors
J. Biol. Chem.
The sensory-efferent function of capsaicin-sensitive sensory neurons
Gen. Pharmacol.
Human α-calcitonin gene-related peptide (8–37) as an antagonist of exogenous and endogenous calcitonin gene-related peptide
Eur. J. Pharmacol.
Distribution of neuronal cannabinoid receptor in the adult rat brain: a comparative receptor binding radioautography and in situ hybridization histochemistry
Neuroscience
Endocannabinoids
Eur. J. Pharmacol.
Imidazoline binding sites and receptors in cardiovascular tissue
Gen. Pharmacol.
Activation of capsaicin-sensitive primary sensory neurones induces anandamide production and release
J. Neurochem.
Cardiovascular effects of intravenous delta-9-tetrahydrocannabinol: autonomic nervous mechanisms
Clin. Pharmacol. Ther.
Reduction by Δ9-tetrahydrocannabinol in the blood pressure of hypertensive rats bearing regenerated adrenal glands
Br. J. Pharmacol.
N-acyl-dopamines: novel synthetic CB1 cannabinoid-receptor ligands and inhibitors of anandamide inactivation with cannabimimetic activity in vitro and in vivo
Biochem. J.
Dual activation and inhibition of adenylyl cyclase by cannabinoid receptor agonists: evidence for agonist-specific trafficking of intracellular responses
J. Pharmacol. Exp. Ther.
Expression of the CB1 and CB2 receptor messenger RNAs during embryonic development in the rat
Neuroscience
CB1 receptor antagonist SR141716A inhibits Ca2+-induced relaxation in CB1 receptor-deficient mice
Hypertension
Autonomic neuromuscular junctions: current developments and future directions
J. Anat.
Co-transmission. The fifth Heymans memorial lecture
Arch. Int. Pharmacodyn. Ther.
Cotransmission
The medicinal use of cannabis among the Greeks and Romans
J. Cannabis Ther.
The vanilloid receptor: a molecular gateway to the pain pathway
Annu. Rev. Neurosci.
The capsaicin receptor: a heat-activated ion channel in the pain pathway
Nature
Impaired nociception and pain sensation in mice lacking the capsaicin receptor
Science
The endothelial component of cannabinoid-induced relaxation in rabbit mesenteric artery depends on gap junctional communication
J. Physiol.
Direct inhibition of T-type calcium channels by the endogenous cannabinoid anandamide
EMBO J.
Pharmacological analysis of cannabinoid receptor activity in the rat vas deferens
Br. J. Pharmacol.
Inhibition by cannabinoid receptor agonists of acetylcholine release from the guinea-pig myenteric plexus
Br. J. Pharmacol.
Evidence that cannabinoid-induced inhibition of electrically evoked contractions of the myenteric plexus-longitudinal muscle preparation of guinea pig small intestine can be modulated by Ca2+ and cAMP
Can. J. Physiol. Pharm.
A possible role of lipoxygenase in the activation of vanilloid receptors by anandamide in the guinea-pig bronchus
Br. J. Pharmacol.
In vitro evidence of neuronal cannabinoid CB1 receptors in human ileum
Br. J. Pharmacol.
Vanilloid receptor-1 is essential for inflammatory thermal hyperalgesia
Nature
Production and physiological actions of anandamide in the vasculature of the rat kidney
J. Clin. Invest.
Cited by (55)
Cannabinoids as multifaceted compounds
2023, PhytochemistryA comparison of the effect of the active release and muscle energy techniques on the latent trigger points of the upper trapezius
2017, Journal of Bodywork and Movement TherapiesCannabis and bioactive cannabinoids
2015, Studies in Natural Products ChemistryExperimental colitis in mice is attenuated by changes in the levels of endocannabinoid metabolites induced by selective inhibition of fatty acid amide hydrolase (FAAH)
2014, Journal of Crohn's and ColitisCitation Excerpt :The principal sites of action for cannabinoids are the “classical” CB receptors, i.e. CB1 and CB2. CB1 receptors are located primarily presynaptically on the surface of nerve cells of the central and the peripheral nervous system, and also in the peripheral tissues like cardiovascular tissue, urinary bladder and gastrointestinal (GI) tract (small intestine, spleen).8,9 CB2 receptors are located mainly on cells of the immune system (e.g. macrophages, neutrophils), but were also detected in the microglial cells and neurons of the CNS.8,9
Possible social relevance of illicit psychotropic substances present in the atmosphere
2011, Science of the Total EnvironmentCannabinoids and the gut: New developments and emerging concepts
2010, Pharmacology and Therapeutics