http://onlinelibrary.wiley.com/doi/10.1111/bph.12642/full
This themed section of BJP arises from the 6th
European Workshop on Cannabinoid Research held in Dublin, Ireland from
18–20 April 2013. The section brings together 3 reviews and 10 research
articles, presenting a range of work across the cannabinoid field.
The review article by Fagan et al. (2014)
addresses the impact of endogenous, plant-derived and synthetic
cannabinoids on neuronal viability. This review summarizes common
mechanisms of neurodegeneration (including mitochondrial dysfunction,
neuroinflammation and excitotoxicity) in three prominent age-related
neurodegenerative disorders, Alzheimers' disease, Parkinson's disease
and Huntington's disease. The review focuses on literature highlighting
the cannabinoid system as a bona fide therapeutic target against such
neurodegenerative processes. In addition, this review brings us
up-to-date on the close links between the endocannabinoid system, ageing
and the process of adult neurogenesis.
Stanley and O'Sullivan (2014)
review the vascular targets of cannabinoids. They examine the evidence
for the range of receptors activated by cannabinoids in perfused
vascular beds or isolated arteries. Direct targets of synthetic,
plant-derived or endogenous cannabinoids include CB1, CBe, TRPV1, peroxisome proliferator-activated receptors (PPARs), CB2, GPR55 and 5-HT1A
receptors. Prostanoid receptors and the calcitonin gene-related peptide
(CGRP) receptor can also indirectly mediate the vascular response to
cannabinoids. Typically cannabinoids have vasorelaxant effects, although
vasoconstriction has also been observed in some instances. Animal and
human studies are reviewed.
The third
review article discusses one of the most abundant endocannabinoids,
2-arachidonylglycerol (2-AG), and summarizes the latest major
discoveries associated with the complex pathways leading to 2-AG
synthesis and metabolism in the central nervous system (CNS) (Murataeva et al., 2014).
This review addresses the spatial and temporal expression of
diacylglycerol lipases (DAGL) in the CNS, the most heavily studied
pathway for 2-AG synthesis. Intriguing questions regarding 2-AG
metabolizing enzymes are considered, including their activity in
different cellular compartments and their contribution to endogenous
2-AG-based signalling. The review highlights that the various enzymes
for synthesizing and degrading 2-AG represent potential therapeutic
targets for neurodegenerative and inflammatory diseases.
Research
on the function of 2-AG has been facilitated in recent years by the
availability of some selective and potent inhibitors of the catabolising
enzyme monoacylglycerol lipase (MAGL). One such inhibitor is the
compound KML29 and Ignatowska-Jankowska et al. (2014)
present novel data herein on the effects of this MAGL inhibitor in
mouse models of inflammatory (carrageenan) and neuropathic (sciatic
nerve injury) pain. Their results show that systemic administration of
KML29 attenuates carrageenan-induced paw oedema and reverses
carrageenan-induced mechanical allodynia. Tolerance to these effects of
KML29 and CB1 receptor desensitization developed after
repeated administration of high doses. Moreover, KML29 partially
reversed sciatic nerve injury-induced allodynia and prevented
diclofenac-induced gastric haemorrhages, without eliciting
cannabimimetic effects in the tetrad test. These preclinical data
suggest that MAGL inhibitors show promise as novel analgesics with a
favourable side-effect profile.
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