Dynamic changes to the endocannabinoid system in models of chronic pain

Sagar, Devi Rani; Burston, James J.; Woodhams, Stephen G; Chapman, Victoria

doi:10.1098/rstb.2011.0390

Cited by 71 publications

(47 citation statements)

References 117 publications

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“…Upregulation of PNOC was associated with mechanical sensitivity of the painful back region in the acute LBP group, suggesting a role in contributing to peripheral sensitization. We also found upregulated cannabinoid type-2 (CB2) receptor ( CNR2 ) gene expression consistent with the findings in a post-mortem study and vast preclinical literature that the CB2 receptor and endocannabinoid system play an important role in modulating pain sensitivity [44, 45]. As increased expression of the CNR2 gene has been associated with reduced pain sensitivity, it remains unclear why higher expression levels were found in the acute LBP group.…”

Section: Discussionsupporting

confidence: 87%

Acute Low Back Pain

Starkweather

Ramesh

Lyon

et al. 2016

The Clinical Journal of Pain

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Objectives Low back pain is the second most frequently diagnosed pain condition in the United States’ and although a majority of individuals have resolution of pain during the acute period, an estimated 40% of individuals will experience persistent pain. Given the heterogenous nature of low back pain, this study sought to describe and compare somatosensory and molecular (gene expression) profiles between individuals with acute low back pain and healthy no-pain controls Methods Using a previously established protocol, we comprehensively assessed somatosensory parameters among 31 no-pain control participants and 31 participants with acute low back pain. Samples of whole blood were drawn to examine mRNA expression of candidate genes involved in the transduction, maintenance, and modulation of pain. Results The acute low back pain group exhibited increased pain sensitivity to cold stimuli, mechanical stimuli, including mechanical temporal summation at both the painful back area and remote location suggesting a mechanism of enhanced central nervous system excitability. In addition, deep tissue specific peripheral sensitization was suggested due to significant differences in pressure pain threshold of the painful back area, but not the remote body site. Several genes that were differentially expressed were significantly associated with somatosensory alterations identified in the acute low back pain group. Discussion Acute low back pain participants showed selective pain sensitivity enhancement and differential gene expression profiles compared to pain-free controls. Further research to characterize pain-associated somatosensory changes in the context of altered mRNA expression levels may provide insight on the molecular underpinnings of maladaptive chronic pain.

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Section: Discussionsupporting

confidence: 87%

Acute Low Back Pain

Starkweather

Ramesh

Lyon

et al. 2016

The Clinical Journal of Pain

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“…Recent studies have advanced understanding of the spinal mechanisms contributing to OA pain behaviour, demonstrating important contributions of dorsal horn neuronal excitability (Sagar et al, ; Kelly et al, ) and activation of spinal glia cells (Lee et al, ; Sagar et al, ; Ogbonna et al, ; Yu et al, ) (see references in Rani Sagar et al, ). In the present study, repeated MJN110 treatment did not significantly inhibit MIA‐induced increases in GFAP mRNA in the dorsal horn of the spinal cord, which contrasts with the reported effects of an exogenous cannabinoid ligand selective for the CB 2 receptor (Burston et al, ).…”

Section: Discussionmentioning

confidence: 99%

“…The endogenous cannabinoid system (ECS), which is composed of two well‐characterized receptors (CB 1 and CB 2 ), endogenous ligands and several biosynthetic and metabolic enzymes, is increasingly recognized for its ability to modulate pain and inflammation, as well as its pharmacological tractability. The ECS modulates nociceptive signalling in numerous preclinical models of pain (see Rani Sagar et al, ). Clinical applications of direct CB 1 receptor agonists indicate that ECS‐targeting agents do offer therapeutic benefit for the treatment of pain in preclinical pain models, as well as in different human pain states (Elikkottil et al, ).…”

Section: Introductionmentioning

confidence: 99%

“…One promising approach for harnessing the analgesic potential of the ECS is to target the catabolic enzymes that regulate levels of endocannabinoids. To date, there has been a predominant focus on protecting levels of the endocannabinoid anandamide (AEA) by the inhibition of fatty acid amide hydrolase (FAAH); however, clinical benefit has yet to be demonstrated (see Rani Sagar et al, ) and a clinical trial of an FAAH inhibitor for OA pain reported no positive benefit over placebo (Huggins et al, ). Unlike AEA, the endocannabinoid 2‐arachidonoylglycerol (2‐AG) is a full efficacy agonist at CB 1 and CB 2 receptors (Savinainen et al, ) and activates both CB 1 and CB 2 receptors with similar potency.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Robust anti‐nociceptive effects of monoacylglycerol lipase inhibition in a model of osteoarthritis pain

Burston

Mapp

Sarmad

et al. 2016

British J Pharmacology

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BACKGROUND AND PURPOSEChronic pain is often a symptom of knee osteoarthritis (OA) for which current analgesics are either inadequate or are associated with serious side effects. The endocannabinoid system may offer alternative targets for pain relief. We evaluated the effects of a potent and selective monoacylglycerol (MAG) lipase inhibitor (MJN110) on OA pain behaviour, spinal mechanisms of action and joint histopathology in the rat. EXPERIMENTAL APPROACHIntra-articular injection of monosodium iodoacetate (MIA) models OA pain and mimics clinical joint pathology. Effects of MJN110 on MIA-induced weight-bearing asymmetry and lowered paw withdrawal thresholds (PWTs), changes in spinal gene expression and brain levels of relevant lipids were determined. KEY RESULTSAcute MJN110 (5 mg·kg À1 ) significantly reversed MIA-induced weight-bearing asymmetry (MIA/vehicle: 68 ± 6 g; MIA/MJN110: 35 ± 4 g) and lowered ipsilateral PWTs (MIA/vehicle: 7 ± 0.8 g; MIA/MJN110: 11 ± 0.6 g), via both CB 1 and CB 2 receptors. Repeated treatment with MJN110 (5 mg·kg À1 ) resulted in anti-nociceptive tolerance. A lower dose of MJN110 (1 mg·kg À1 ) acutely inhibited pain behaviour, which was maintained for 1 week of repeated administration but had no effect on joint histology. MJN110 significantly inhibited expression of membrane-associated PGE synthase-1 in the ipsilateral dorsal horn of the spinal cord of MIA rats, compared with vehicle-treated MIA rats. Both doses of MJN110 significantly elevated brain levels of the endocannabinoid 2-arachidonoylglycerol. CONCLUSIONS AND IMPLICATIONSOur data support further assessment of the therapeutic potential of MAG lipase inhibitors for the treatment of OA pain. Abbreviations

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“…Their side-effect profile, however, has driven the search for alternative cannabinoid-based approaches to analgesia. Dynamic changes in the ECS, which are associated with chronic pain states, provide new opportunities for cannabinoidmediated modulation of nociceptive processing, a topic which Chapman and co-workers [38] pick-up on. Starting with an overview of current knowledge on the impact of chronic pain states on the key components of the endocannabinoid receptor system, we learn of localized changes in receptor expression and levels of key metabolic enzymes which influence endocannabinoid local levels.…”

Section: The Many Facets Of Endocannabinoidsmentioning

confidence: 99%

Endocannabinoids in nervous system health and disease: the big picture in a nutshell

Skaper

Marzo²

2012

Phil. Trans. R. Soc. B

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The psychoactive component of the cannabis resin and flowers, delta9-tetrahydrocannabinol (THC), was first isolated in 1964, and at least 70 other structurally related 'phytocannabinoid' compounds have since been identified. The serendipitous identification of a G-protein-coupled cannabinoid receptor at which THC is active in the brain heralded an explosion in cannabinoid research. Elements of the endocannabinoid system (ECS) comprise the cannabinoid receptors, a family of nascent lipid ligands, the 'endocannabinoids' and the machinery for their biosynthesis and metabolism. The function of the ECS is thus defined by modulation of these receptors, in particular, by two of the best-described ligands, 2-arachidonoyl glycerol and anandamide (arachidonylethanolamide). Research on the ECS has recently aroused enormous interest not only for the physiological functions, but also for the promising therapeutic potentials of drugs interfering with the activity of cannabinoid receptors. Many of the former relate to stress-recovery systems and to the maintenance of homeostatic balance. Among other functions, the ECS is involved in neuroprotection, modulation of nociception, regulation of motor activity, neurogenesis, synaptic plasticity and the control of certain phases of memory processing. In addition, the ECS acts to modulate the immune and inflammatory responses and to maintain a positive energy balance. This theme issue aims to provide the reader with an overview of ECS pharmacology, followed by discussions on the pivotal role of this system in the modulation of neurogenesis in the developing and adult organism, memory processes and synaptic plasticity, as well as in pathological pain and brain ageing. The volume will conclude with discussions that address the proposed therapeutic applications of targeting the ECS for the treatment of neurodegeneration, pain and mental illness.

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Dynamic changes to the endocannabinoid system in models of chronic pain

Cited by 71 publications

References 117 publications

Acute Low Back Pain

Acute Low Back Pain

Robust anti‐nociceptive effects of monoacylglycerol lipase inhibition in a model of osteoarthritis pain

Endocannabinoids in nervous system health and disease: the big picture in a nutshell

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