Review
Cannabinoid modulation of peripheral autonomic and sensory neurotransmission

https://doi.org/10.1016/S0014-2999(03)01813-2Get rights and content

Abstract

Cannabinoids are cell membrane-derived signalling molecules that are released from nerves, blood cells and endothelial cells, and have diverse biological effects. They act at two distinct types of G-protein-coupled receptors, cannabinoid CB1 and CB2 receptors. Cannabinoid CB1 receptors are highly localised in the central nervous system and are also found in some peripheral tissues, and cannabinoid CB2 receptors are found outside the central nervous system, in particular in association with immune tissues. Novel actions of cannabinoids at non-CB1 non-CB2 cannabinoid-like receptors and vanilloid VR1 receptors have also recently been described. There is growing evidence that, among other roles, cannabinoids can act at prejunctional sites to modulate peripheral autonomic and sensory neurotransmission, and the present article is aimed at providing an overview of this. Inhibitory cannabinoid CB1 receptors are expressed on the peripheral terminals of autonomic and sensory nerves. The role of cannabinoid receptor ligands in modulation of sensory neurotransmission is complex, as certain of these (anandamide, an “endocannabinoid”, and N-arachidonoyl-dopamine, an “endovanilloid”) also activate vanilloid VR1 receptors (coexpressed with cannabinoid CB1 receptors), which excites sensory nerves and causes a release of sensory neurotransmitter. The fact that the activities of anandamide and N-arachidonoyl-dopamine span two distinct receptor families raises important questions about cannabinoid/vanilloid nomenclature, and as both compounds are structurally related to the archetypal vanilloid capsaicin, all three are arguably members of the same family of signalling molecules. Anandamide is released from nerves, but unlike classical neurotransmitters, it is not stored in and released from nerve vesicles, but is released on demand from the nerve cell membrane. In the central nervous system, cannabinoids function as retrograde signalling molecules, inhibiting via presynaptic cannabinoid CB1 receptors the release of classical transmitter following release from the postsynaptic cell. At the neuroeffector junction, it is more likely that cannabinoids are released from prejunctional sites, as the neuroeffector junction is wide in some peripheral tissues and cannabinoids are rapidly taken up and inactivated. Understanding the actions of cannabinoids as modulators of peripheral neurotransmission is relevant to a variety of biological systems and possibly their disorders.

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)

  • G. Griffin et al.

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

    Eur. J. Pharmacol.

    (1997)
  • T. Himmi et al.

    Neuronal responses to cannabinoid receptor ligands in the solitary tract nucleus

    Eur. J. Pharmacol.

    (1998)
  • G.D.S. Hirst et al.

    Transmission by post-ganglionic axons of the autonomic nervous system: the importance of the specialized neuroeffector junction

    Neuroscience

    (1996)
  • A.G. Hohmann

    Spinal and peripheral mechanisms of cannabinoid antinociception: behavioural, neurophysiological and neuroanatomical perspectives

    Chem. Phys. Lipids

    (2002)
  • A.G. Hohmann et al.

    Localization of central cannabinoid CB1 receptor messenger RNA in neuronal subpopulations of rat dorsal root ganglia: a double-label in situ hybridization study

    Neuroscience

    (1999)
  • A.G. Hohmann et al.

    Cannabinoid receptors undergo axonal flow in sensory nerves

    Neuroscience

    (1999)
  • A.A. Izzo et al.

    The gastrointestinal pharmacology of cannabinoids

    Curr. Opin. Pharmacol.

    (2001)
  • B.S. Jandhyala et al.

    Pulmonary and systemic hemodynamic effects of Δ9-tetrahydrocannabinol in conscious and morphine-chloralose-anesthetised dogs: anesthetic influence on drug action

    Eur. J. Pharmacol.

    (1978)
  • A.C. Kreitzer et al.

    Retrograde signaling by endocannabinoids

    Curr. Opin. Neurobiol.

    (2002)
  • R.S. Landsman et al.

    SR141716A is an inverse agonist at the human cannabinoid CB1 receptor

    Eur. J. Pharmacol.

    (1997)
  • L. Lay et al.

    Pharmacological characterisation of cannabinoid CB1 receptors in the rat and mouse

    Eur. J. Pharmacol.

    (2000)
  • M. Maccarrone et al.

    Anandamide induces apoptosis in human cells via vanilloid receptors—evidence for a protective role of cannabinoid receptors

    J. Biol. Chem.

    (2000)
  • C.A. Maggi et al.

    The sensory-efferent function of capsaicin-sensitive sensory neurons

    Gen. Pharmacol.

    (1988)
  • C.A. Maggi et al.

    Human α-calcitonin gene-related peptide (8–37) as an antagonist of exogenous and endogenous calcitonin gene-related peptide

    Eur. J. Pharmacol.

    (1991)
  • P. Mailleux et al.

    Distribution of neuronal cannabinoid receptor in the adult rat brain: a comparative receptor binding radioautography and in situ hybridization histochemistry

    Neuroscience

    (1992)
  • R. Mechoulam et al.

    Endocannabinoids

    Eur. J. Pharmacol.

    (1998)
  • G.J. Molderings et al.

    Imidazoline binding sites and receptors in cardiovascular tissue

    Gen. Pharmacol.

    (1999)
  • J. Ahluwalia et al.

    Activation of capsaicin-sensitive primary sensory neurones induces anandamide production and release

    J. Neurochem.

    (2003)
  • N.L. Benowitz et al.

    Cardiovascular effects of intravenous delta-9-tetrahydrocannabinol: autonomic nervous mechanisms

    Clin. Pharmacol. Ther.

    (1979)
  • M.K. Birmingham

    Reduction by Δ9-tetrahydrocannabinol in the blood pressure of hypertensive rats bearing regenerated adrenal glands

    Br. J. Pharmacol.

    (1973)
  • T. Bisogno et al.

    N-acyl-dopamines: novel synthetic CB1 cannabinoid-receptor ligands and inhibitors of anandamide inactivation with cannabimimetic activity in vitro and in vivo

    Biochem. J.

    (2000)
  • D.W. Bonhaus et al.

    Dual activation and inhibition of adenylyl cyclase by cannabinoid receptor agonists: evidence for agonist-specific trafficking of intracellular responses

    J. Pharmacol. Exp. Ther.

    (1998)
  • N.E. Buckley et al.

    Expression of the CB1 and CB2 receptor messenger RNAs during embryonic development in the rat

    Neuroscience

    (1998)
  • R.D. Bukoski et al.

    CB1 receptor antagonist SR141716A inhibits Ca2+-induced relaxation in CB1 receptor-deficient mice

    Hypertension

    (2002)
  • G. Burnstock

    Autonomic neuromuscular junctions: current developments and future directions

    J. Anat.

    (1986)
  • G. Burnstock

    Co-transmission. The fifth Heymans memorial lecture

    Arch. Int. Pharmacodyn. Ther.

    (1990)
  • G. Burnstock et al.

    Cotransmission

  • J.L. Butrica

    The medicinal use of cannabis among the Greeks and Romans

    J. Cannabis Ther.

    (2002)
  • M.J. Caterina et al.

    The vanilloid receptor: a molecular gateway to the pain pathway

    Annu. Rev. Neurosci.

    (2001)
  • M.J. Caterina et al.

    The capsaicin receptor: a heat-activated ion channel in the pain pathway

    Nature

    (1997)
  • M.J. Caterina et al.

    Impaired nociception and pain sensation in mice lacking the capsaicin receptor

    Science

    (2000)
  • A.T. Chaytor et al.

    The endothelial component of cannabinoid-induced relaxation in rabbit mesenteric artery depends on gap junctional communication

    J. Physiol.

    (1999)
  • J. Chemin et al.

    Direct inhibition of T-type calcium channels by the endogenous cannabinoid anandamide

    EMBO J.

    (2001)
  • A. Christopoulos et al.

    Pharmacological analysis of cannabinoid receptor activity in the rat vas deferens

    Br. J. Pharmacol.

    (2001)
  • A.A. Coutts et al.

    Inhibition by cannabinoid receptor agonists of acetylcholine release from the guinea-pig myenteric plexus

    Br. J. Pharmacol.

    (1997)
  • A.A. Coutts et al.

    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.

    (1998)
  • S.J. Craib et al.

    A possible role of lipoxygenase in the activation of vanilloid receptors by anandamide in the guinea-pig bronchus

    Br. J. Pharmacol.

    (2001)
  • T. Croci et al.

    In vitro evidence of neuronal cannabinoid CB1 receptors in human ileum

    Br. J. Pharmacol.

    (1998)
  • J.B. Davis et al.

    Vanilloid receptor-1 is essential for inflammatory thermal hyperalgesia

    Nature

    (2000)
  • D.G. Deutsch et al.

    Production and physiological actions of anandamide in the vasculature of the rat kidney

    J. Clin. Invest.

    (1997)
  • Cited by (55)

    • Cannabis and bioactive cannabinoids

      2015, Studies in Natural Products Chemistry
    • Experimental 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 Colitis
      Citation 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

    View all citing articles on Scopus
    View full text