Spinal Cannabinoids – a Double-Edged Sword? (Commentary on Zhang Et Al.)

European Journal of Neuroscience

European Journal of Neuroscience, Vol. 31, pp. 223–224, 2010 doi:10.1111/j.1460-9568.2010.07125.x

SYNAPTIC MECHANISMS

COMMENTARY Spinal cannabinoids – a double-edged sword? (Commentary on Zhang et al.)

Hanns Ulrich Zeilhofer1,2 1Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland 2Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology (ETH) Zurich, Zurich, Switzerland

The prototypical effects of the cannabis extract delta9-tetrahydrocannabinol (THC) are characterized by a tetrad of actions, consisting of analgesia, catalepsy, sedation, and hypothermia, all of which are mediated by activation of CB1 receptors. Initial studies of the cellular distribution of CB1 receptors have indicated that they are located primarily on axon terminals of GABAergic interneurons, and their most obvious cellular action is a reduction in transmitter release at these inhibitory synapses. However, the behavioral effects of THC are attenuated by removing CB1 receptors from cortical and striatal projection neurons (Monory et al., 2007). Collectively, these findings indicate that complex physiological mechanisms mediate the effects of cannabinoids and CB1 receptor stimulation. This complexity is also apparent in the spinal dorsal horn, a CNS area critically involved in the processing of pain signals, as highlighted in the study by Zhang et al. (2010) published in this issue of EJN. Part of the analgesic action of cannabinoids is believed to originate from blockade of excitatory neurotransmission between C-fiber nociceptors and central neurons located in the spinal dorsal horn and trigeminal sensory nucleus (Morisset & Urban, 2001; Liang et al., 2004). Yet, when studied at a cellular level, the most prominent action of CB1 receptor activation again is a reduction in GABAergic and glycinergic inhibition mediated by dorsal horn interneurons (Jennings et al., 2001; Pernia-Andrade et al., 2009). In this issue of EJN, Zhang et al. (2010) used a new approach to quantify the effect of CB1 receptor activation on nociceptive transmission. In slices of rat spinal cord with incoming sensory nerve fibers attached, they electrically stimulated incoming C-fiber nociceptors to evoke neurotransmitter release from these axons. About half of these nociceptors, specifically the peptidergic subpopulation, co-release glutamate and the neuropeptide substance P. Substance P acts on postsynaptic neurokinin 1 (NK1) receptors. These NK1 receptors are G protein-coupled receptors, which are removed from the cell surface through internalization after activation by substance P. The number of cells showing internalization of NK1 receptor can thus be used as an index of substance P release and, therefore, of the density of nociceptive input to the spinal dorsal horn. Rather unexpectedly, the authors found that CB1 receptor activation increased rather than decreased NK1 receptor internalization. Together with the findings from appropriate controls described in this study, this result indicates that CB1 receptor activation leads to increased substance P release, suggesting a pronociceptive action. Indeed, the authors demonstrate that AM251, an antagonist (or strictly speaking an inverse agonist) at CB1 receptors, possesses antinociceptive properties against noxious heat stimuli. The authors explain this surprising result primarily by a disinhibitory action of spinal CB1 receptors. According to their model, substance P release by C-fiber nociceptors is modulated indirectly by endocannabinoids acting on inhibitory interneuron terminals, which release GABA and opioid peptides to activate presynaptic GABAB and l-opioid receptors located on C-fiber nociceptors. Their model is supported by evidence showing that numerous inhibitory (GABAergic and glycinergic) axon terminals carry functional CB1 receptors. By activating these CB1 receptors, THC would reduce presynaptic inhibition of C-fiber nociceptors, thereby allowing increased substance P release. However, this model apparently contradicts previously published results indicating the presence of CB1 receptors on peptidergic, substance P-releasing, C-fiber nociceptors. Nyilas et al. (2009) (cited by authors) localized CB1 receptors on spinal nociceptor terminals, and Hegyi et al. (2009) demonstrated that CB1 receptor immunoreactivity co-localizes with CGRP and IB4, markers of peptidergic and non-peptidergic C-fiber terminals, respectively. Moreover, in mouse models of inflammatory and neuropathic pain, spinal injection of the CB1 receptor agonist, CP 55 940 causes analgesia in wild type mice, but not in CB1 receptor-deficient mice (Pernia-Andrade et al., 2009). However, antinociceptive effects of CB1 receptor antagonists (or inverse agonists) were previously reported in certain models of inflammatory or activity-dependent hyperalgesia (Croci & Zarini, 2007; Pernia-Andrade et al., 2009) as well as in a hypoalgesic phenotype of mice lacking CB1 receptors in formalin-induced pain (Zimmer et al., 1999). An explanation is required to reconcile the model presented by Zhang et al. (2010) with the findings described in this literature. One such explanation suggests that the coupling of CB1 receptors to down-stream effectors such as G proteins and ion channels changes differentially in excitatory and inhibitory neurons during pathological pain states, favoring disinhibition of nociceptor terminals under physiological conditions, but inhibition in pathological pain states. Alternatively, cannabinoid-mediated spinal analgesia might be elicited through completely different mechanisms. Hegyi et al. (2009) showed that CB1 receptors in the spinal cord dorsal horn are not only found on neurons but also on half of the astrocytes and on the majority of microglia cells. Both types of glia cells contribute to pathological pain syndromes (Miraucourt et al., 2007; Inoue & Tsuda, 2009) and a CB1 receptor-dependent regulation of these cells might very well contribute to cannabinoid-mediated spinal analgesia. Regardless of the eventual explanation for these discrepant results, increasing evidence indicates that the action cannabinoids and CB1 receptors in vivo is more complex than apparent ex-vivo. The study by Zhang et al. (2010) will certainly not remain the last surprise in cannabinoid research.

ª The Author (2010). Journal Compilation ª Federation of European Neuroscience Societies and Blackwell Publishing Ltd 224 Commentary

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ª The Author (2010). Journal Compilation ª Federation of European Neuroscience Societies and Blackwell Publishing Ltd European Journal of Neuroscience, 31, 223–224