Review
Possible mechanisms of cannabinoid-induced antinociception in the spinal cord

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Abstract

Anandamide is an endogenous ligand at both the inhibitory cannabinoid CB1 receptor and the excitatory vanilloid receptor 1 (VR1). The CB1 receptor and vanilloid VR1 receptor are expressed in about 50% and 40% of dorsal root ganglion neurons, respectively. While all vanilloid VR1 receptor-expressing cells belong to the calcitonin gene-related peptide-containing and isolectin B4-binding sub-populations of nociceptive primary sensory neurons, about 80% of the cannabinoid CB1 receptor-expressing cells belong to those sub-populations. Furthermore, all vanilloid VR1 receptor-expressing cells co-express the cannabinoid CB1 receptor. In agreement with these findings, neonatal capsaicin treatment that induces degeneration of capsaicin-sensitive, vanilloid VR1 receptor-expressing, thin, unmyelinated, nociceptive primary afferent fibres significantly reduced the cannabinoid CB1 receptor immunostaining in the superficial spinal dorsal horn. Synthetic cannabinoid CB1 receptor agonists, which do not have affinity at the vanilloid VR1 receptor, and low concentrations of anandamide both reduce the frequency of miniature excitatory postsynaptic currents and electrical stimulation-evoked or capsaicin-induced excitatory postsynaptic currents in substantia gelatinosa cells in the spinal cord without any effect on their amplitude. These effects are blocked by selective cannabinoid CB1 receptor antagonists. Furthermore, the paired-pulse ratio is increased while the postsynaptic response of substantia gelatinosa neurons induced by α-amino-3-hydroxy-5-methylisoxasole-propionic acid (AMPA) in the presence of tetrodotoxin is unchanged following cannabinoid CB1 receptor activation. These results strongly suggest that the cannabinoid CB1 receptor is expressed presynaptically and that the activation of these receptors by synthetic cannabinoid CB1 receptor agonists or low concentration of anandamide results in inhibition of transmitter release from nociceptive primary sensory neurons. High concentrations of anandamide, on the other hand, increase the frequency of miniature excitatory postsynaptic currents recorded from substantia gelatinosa neurons. This increase is blocked by ruthenium red, suggesting that this effect is mediated through the vanilloid VR1 receptor. Thus, anandamide at high concentrations can activate the VR1 and produce an opposite, excitatory effect to its inhibitory action produced at low concentrations through cannabinoid CB1 receptor activation. This “dual”, concentration-dependent effect of anandamide could be an important presynaptic modulatory mechanism in the spinal nociceptive system.

Introduction

Derivatives of cannabis sativa, endogenous ligands of the cannabinoid CB1 receptor, such as anandamide and 2-arachidonoylglycerol, synthetic cannabinoid CB1 receptor agonist molecules and inhibitors of the cannabinoid re-uptake system have been shown to produce antinociceptive or antihyperalgesic effects in various animal models of pain Calignano et al., 1998, Herzberg et al., 1997, Mao et al., 2000, Martin et al., 1998, Martin et al., 1999, Mazzari et al., 1996, Richardson et al., 1998a, Richardson et al., 1998b, Smith et al., 1998, Strangman et al., 1998, Vivian et al., 1998, Welch et al., 1998. In addition, there is anecdotal clinical evidence that marijuana-smoking attenuates pain in multiple sclerosis patients (Consroe et al., 1997).

Cannabinoids activate two known receptor subtypes: the cannabinoid CB1 and CB2 receptors. The cannabinoid CB1 receptor is broadly found in the central and peripheral nervous systems, while the cannabinoid CB2 receptor is expressed in non-neuronal cells. The antinociceptive effects of endogenous and exogenous cannabinoids are exerted primarily via the cannabinoid CB1 receptor, which is coupled with Gi/Go proteins Matsuda et al., 1990, Munro et al., 1993. Activation of the cannabinoid CB1 receptor leads to inhibition of adenylyl cyclase activity Felder et al., 1995, Howlett and Fleming, 1984. In addition, cannabinoid CB1 receptor activation inhibits Ca2+ currents Caulfield and Brown, 1992, Twitchell et al., 1997 and modulates various potassium currents Deadwyler et al., 1995, Mackie et al., 1995, Poling et al., 1996 at different sites in the central nervous system (CNS).

In general, cannabinoids inhibit glutamatergic transmission in the brain Levenes et al., 1998, Shen et al., 1996, Szabo et al., 2000 and participate in the control of neuronal excitability and firing McAllister et al., 1999, Mu et al., 1999, Pan et al., 1998, Poling et al., 1996, Schweitzer, 2000, Shen et al., 1996.

Cannabinoid CB1 receptors are expressed in supraspinal Herkenham et al., 1991, Katona et al., 1999, Litchman et al., 1996, Mailleux and Vanderhaeghen, 1995, Martin et al., 1996, Martin et al., 1998, Tsou et al., 1998, spinal Farquhar-Smith et al., 2000, Herkenham et al., 1991, Tsou et al., 1998 and peripheral Ahluwalia et al., 2000, Hohmann and Herkenham, 1999 centres associated with nociceptive processing. Strong immunostaining of cannabinoid CB1 receptors in the dorsal horn and in the dorsal root ganglia suggests that one of the major sites of antinociceptive action is the spinal cord. This is supported by behavioural studies using intrathecal injection of cannabinoid receptor agonists Litchman and Martin, 1991, Mao et al., 2000, Richardson et al., 1998a, Richardson et al., 1998b, Richardson et al., 1998c, electrophysiological extracellular recordings Hohmann et al., 1995, Hohmann et al., 1998, Hohmann et al., 1999 and inhibition of C-fibre induced neurotransmitter release in the spinal cord (Drew et al., 2000).

Section snippets

Anatomical evidence for cannabinoid-induced presynaptic modulation of the spinal nociceptive synaptic transmission

Hohmann and Herkenham (1999) have shown that the spinal binding of cannabinoid CB1 receptor ligands was decreased by about 50% after dorsal rhizotomy suggesting that cannabinoid CB1 receptor are expressed both on primary sensory fibres and other structures in the spinal dorsal horn. However, neonatal capsaicin injection, which induces degeneration of the majority of nociceptive primary sensory neurons, produces only a moderate decrease in cannabinoid receptor binding in the spinal dorsal horn

Functional significance of the cannabinoid CB1 receptor expression on capsaicin-sensitive nociceptive primary sensory neurons

Further evidence for the putative location of cannabinoid CB1 receptors in the spinal dorsal horn has been provided by Morisset and Urban (2001) by using the patch-clamp recording technique in substantia gelatinosa neurons. Synthetic cannabinoids, such as (R)-(+)-[2,3-Dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphtalenylmethanone (WIN55,212-2) reduced the frequency but not the amplitude of miniature excitatory postsynaptic currents (mEPSCs) and EPSCs

Concentration-related effects of anandamide: a dynamic presynaptic modulatory system in the dorsal horn?

An exciting aspect of cannabinoid CB1 receptor and vanilloid VR1 receptor co-expression was raised after recent findings by Zygmund et al. (1999) suggesting that anandamide, the endogenous cannabinoid CB1 receptor ligand, although at high concentrations (Tognetto et al., 2001), also activates the vanilloid VR1 receptor.

We investigated this dual effect of anandamide on nociceptive primary afferents by using patch-clamp recordings from substantia gelatinosa neurons. Anandamide at 1 μM

Summary

In summary, morphological and physiological evidences suggest a strong presynaptic cannabinoid CB1 receptor-mediated modulation of the nociceptive input to substantia gelatinosa neurons in the spinal cord. The attenuation of the capsaicin-induced increase in excitability and depolarisation of the substantia gelatinosa cells suggests that the strong inhibitory effect of the cannabinoids is able to reduce the nociceptive input to the spinal dorsal horn. This strong inhibitory effect is likely to

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