Cannabinoid CB1 receptor upregulation in a rat model of chronic neuropathic pain

doi:10.1016/S0014-2999(01)00798-1

European Journal of Pharmacology

Volume 415, Issue 1, 9 March 2001, Pages R5-R7

https://doi.org/10.1016/S0014-2999(01)00798-1 Get rights and content

Abstract

Although cannabinoids are known to be more effective analgesics against chronic rather than acute pain, the mechanism underlying this phenomenon is still unclear. We report now that contralateral thalamic cannabinoid CB₁ receptors are upregulated after unilateral axotomy of the tibial branch of the sciatic nerve, a rat model of chronic neuropathic pain, and hypothesize that cannabinoid CB₁ receptor upregulation contributes to the increased analgesic efficacy of cannabinoids in chronic pain conditions.

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Acknowledgements

We thank I. Flocke, F. Juengerkes, B. Koenig, I. Kruse, and B. Tretter for expert technical assistance and Dr P. Reeh (Department of Physiology, University of Erlangen-Nuernberg, Germany) for critical reading of the manuscript.

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The CB1 receptor is expressed in the thalamus [2]. The thalamic cannabinoid CB1 receptors are up-regulated in a rat model of chronic neuropathic pain, which maybe contribute to the increased analgesic efficacy of cannabinoids in chronic pain [60], but CB1 receptors did not altered in the present study (data did not shown). A recent study found that the CB1 receptors located at the incerta-thalamic circuit terminals were critical elements in pain control [61].
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This effect was blocked by direct administration of rimonabant into the nucleus reticularis gigantocellularis pars, suggesting that increased endocannabinoid tone in neuropathic rats can modulate nociceptive behavior (Monhemius et al., 2001). In the thalamus, CB1R mRNA is upregulated in a rat model of neuropathic pain (Siegling, Hofmann, Denzer, Mauler, & De Vry, 2001). Potentially, upregulation of thalamic CB1R in neuropathic pain states may serve to enhance the analgesic effects of cannabinoids under these conditions.
The endocannabinoid system, consisting of the cannabinoid₁ receptor (CB₁R) and cannabinoid₂ receptor (CB₂R), endogenous cannabinoid ligands (endocannabinoids), and metabolizing enzymes, is present throughout the pain pathways. Endocannabinoids, phytocannabinoids, and synthetic cannabinoid receptor agonists have antinociceptive effects in animal models of acute, inflammatory, and neuropathic pain. CB₁R and CB₂R located at peripheral, spinal, or supraspinal sites are important targets mediating these antinociceptive effects. The mechanisms underlying the analgesic effects of cannabinoids likely include inhibition of presynaptic neurotransmitter and neuropeptide release, modulation of postsynaptic neuronal excitability, activation of the descending inhibitory pain pathway, and reductions in neuroinflammatory signaling. Strategies to dissociate the psychoactive effects of cannabinoids from their analgesic effects have focused on peripherally restricted CB₁R agonists, CB₂R agonists, inhibitors of endocannabinoid catabolism or uptake, and modulation of other non-CB₁R/non-CB₂R targets of cannabinoids including TRPV1, GPR55, and PPARs. The large body of preclinical evidence in support of cannabinoids as potential analgesic agents is supported by clinical studies demonstrating their efficacy across a variety of pain disorders.
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Cannabinoids have shown to have a variety effects on body systems. Through CB1 and CB2 receptors, amongst other, they exert an effect by modulating neurotransmitter and cytokine release. Current research in the role of cannabinoids in the immune system shows that they possess immunosuppressive properties. They can inhibit proliferation of leucocytes, induce apoptosis of T cells and macrophages and reduce secretion of pro-inflammatory cytokines. In mice models, they are effective in reducing inflammation in arthritis, multiple sclerosis, have a positive effect on neuropathic pain and in type 1 diabetes mellitus. They are effective as treatment for fibromyalgia and have shown to have anti-fibrotic effect in scleroderma. Studies in human models are scarce and not conclusive and more research is required in this field. Cannabinoids can be therefore promising immunosuppressive and anti-fibrotic agents in the therapy of autoimmune disorders.
Dissociation between the panicolytic effect of cannabidiol microinjected into the substantia nigra, pars reticulata, and fear-induced antinociception elicited by bicuculline administration in deep layers of the superior colliculus: The role of CB<inf>1</inf>-cannabinoid receptor in the ventral mesencephalon
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In experimental models of chronic pain, there is an increase in the expression of these receptors (Manzanares et al., 2006). For example, models of neuropathic pain stimulate the expression and regulation of CB1 receptors in structures involved in pain processing, such as the superficial laminas of the dorsal horn of the spinal cord (Lim et al., 2003) and contralateral dorsal thalamic nuclei (Siegling et al., 2001). The aim of the present study was to investigate the effects of central administration of CBD into the substantia nigra, pars reticulata (SNpr), on GABAA receptor blockade-induced panic-like responses organised by the dorsal midbrain.
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A randomized, double-blinded, placebo controlled crossover study was conducted in 16 patients with painful diabetic peripheral neuropathy to assess the short-term efficacy and tolerability of inhaled cannabis. In a crossover design, each participant was exposed to 4 single dosing sessions of placebo or to low (1% tetrahydrocannabinol [THC]), medium (4% THC), or high (7% THC) doses of cannabis. Baseline spontaneous pain, evoked pain, and cognitive testing were performed. Subjects were then administered aerosolized cannabis or placebo and the pain intensity and subjective “highness” score was measured at 5, 15, 30, 45, and 60 minutes and then every 30 minutes for an additional 3 hours. Cognitive testing was performed at 5 and 30 minutes and then every 30 minutes for an additional 3 hours. The primary analysis compared differences in spontaneous pain over time between doses using linear mixed effects models. There was a significant difference in spontaneous pain scores between doses (P < .001). Specific significant comparisons were placebo versus low, medium, and high doses (P = .031, .04, and <.001, respectively) and high versus low and medium doses (both P < .001). There was a significant effect of the high dose on foam brush and von Frey evoked pain (both P < .001). There was a significant negative effect (impaired performance) of the high dose on 2 of the 3 neuropsychological tests (Paced Auditory Serial Addition Test, Trail Making Test Part B.
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Rapid communicationCannabinoid CB1 receptor upregulation in a rat model of chronic neuropathic pain

Abstract

Section snippets

Acknowledgements

Neurosci. Lett.

TIPS

J. Immunol. Methods

Heat shock protein 27: developmental regulation and expression after peripheral nerve injury

J. Neurosci.

Rapid communication
Cannabinoid CB₁ receptor upregulation in a rat model of chronic neuropathic pain