Cannabis analgesia in chronic neuropathic pain is associated with altered brain connectivity

Libat WeizmanLior DayanSilviu BrillHadas Nahman-AverbuchTalma HendlerGiris JacobHaggai Sharon  (September 2018)

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To characterize the functional brain changes involved in δ-9-tetrahydrocannabinol (THC) modulation of chronic neuropathic pain. THC significantly reduced patients’ pain compared to placebo. THC-induced analgesia was correlated with a reduction in functional connectivity between the anterior cingulate cortex (ACC) and the sensorimotor cortex. Moreover, the degree of reduction was predictive of the response to THC. Graph theory analyses of local measures demonstrated reduction in network connectivity in areas involved in pain processing, and specifically in the dorsolateral prefrontal cortex (DLPFC), which were correlated with individual pain reduction.

The Endogenous Cannabinoid System: A Budding Source of Targets for Treating Inflammatory and Neuropathic Pain

Giulia DonvitoSara R NassJenny L WilkersonZachary A CurryLesley D SchurmanSteven G Kinsey Aron H Lichtman  (August 2017)

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Emerging clinical studies show that ‘medicinal’ cannabis or cannabinoid-based medications relieve pain in human diseases such as cancer, multiple sclerosis, and fibromyalgia. However, clinical data have yet to demonstrate the analgesic efficacy of inhibitors of endocannabinoid-regulating enzymes. Likewise, the question of whether pharmacotherapies aimed at the endocannabinoid system promote opioid-sparing effects in the treatment of pain reflects an important area of research. Here we examine the preclinical and clinical evidence of various endocannabinoid system targets as potential therapeutic strategies for inflammatory and neuropathic pain conditions.

Endocannabinoid activation of CB1 receptors contributes to long‐lasting reversal of neuropathic pain by repetitive spinal cord stimulation

L. Sun, L. Tai, Q. Qiu, R. Mitchell , S. Fleetwood‐Walker,E.A. Joosten,C.W. Cheung  (January 2017)
The endocannabinoid system, and in particular the CB1R, plays a pivotal role in the long‐lasting and incremental reversal of hyperalgesia induced by repetitive SCS in a neuropathic pain model.  Alternative parameters for repetitive spinal cord stimulation (SCS) at 25/10 Hz elicit particularly long‐lasting and incremental reversal of hyperalgesia in a neuropathic pain model through a mechanism involving endocannabinoids.

The endocannabinoid system and neuropathic pain

Rafael MaldonadoJosep Eladi Baños, David Cabañero  (February 2016)

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One of the neurotransmitter systems participating in neuropathic pain control that has recently raised a particular interest is the endocannabinoid system. This system is highly expressed in neurons and immune cells, and it plays a crucial role in the development of neuropathic pain. Preclinical studies have provided important findings, revealing the potential interest of the endocannabinoid system for the treatment of neuropathic pain. These studies have reported the analgesic effects of cannabinoid agonists in multiple neuropathic pain models, and they have identified specific targets within this system to develop more effective and safe analgesic compounds.

A Cannabinoid CB1 Receptor-Positive Allosteric Modulator Reduces Neuropathic Pain in the Mouse with No Psychoactive Effects

Bogna M Ignatowska-JankowskaGemma L BaillieSteven KinseyMolly CroweSudeshna GhoshRobert A OwensImad M DamajJustin PoklisJenny L WileyMatteo ZandaChiara ZanatoIain R GreigAron H Lichtman Ruth A Ross  (June 2015)

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The CB1 receptor represents a promising target for the treatment of several disorders including pain-related disease states. However, therapeutic applications of Δ9-tetrahydrocannabinol and other CB1orthosteric receptor agonists remain limited because of psychoactive side effects. Positive allosteric modulators (PAMs) offer an alternative approach to enhance CB1 receptor function for therapeutic gain with the promise of reduced side effects. Here we describe the development of the novel synthetic CB1 PAM, 6-methyl-3-(2-nitro-1-(thiophen-2-yl)ethyl)-2-phenyl-1H-indole (ZCZ011), which augments the in vitro and in vivo pharmacological actions of the CB1 orthosteric agonists CP55,940 and N-arachidonoylethanolamine (AEA).

Endocannabinoids and neuropathic pain: focus on neuron–glia and endocannabinoid–neurotrophin interactions

Livio Luongo, Sabatino Maione, Vincenzo Di Marzo  (February 2014)
Although originally described as a signalling system encompassing the cannabinoid CB1and CB2 receptors, their endogenous agonists (the endocannabinoids), and metabolic enzymes regulating the levels of such agonists, the endocannabinoid system is now viewed as being more complex, and including metabolically related endocannabinoid‐like mediators and their molecular targets as well. The function and dysfunction of this complex signalling system in the molecular and cellular mechanisms of pain transduction and control has been widely studied over the last two decades. In this review article, we describe some of the latest advances in our knowledge on the role of the endocannabinoid system, in its most recent and wider conception, in pain pathways, by focusing on: (1) neuron–glia interactions; and (2) emerging data on endocannabinoid cross‐talk with neurotrophins, such as nerve growth factor and brain‐derived neurotrophic factor.

Blockade of Endocannabinoid-Degrading Enzymes Attenuates Neuropathic Pain

S.G. KinseyJ.Z. LongS.T. O’NealR.A. AbdullahJ.L. PoklisD.L. BogerB.F. Cravatt and A.H. Lichtman  (September 2009)

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Direct-acting cannabinoid receptor agonists are well known to reduce hyperalgesic responses and allodynia after nerve injury, although their psychoactive side effects have damped enthusiasm for their therapeutic development. Alternatively, inhibiting fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), the principal enzymes responsible for the degradation of the respective endogenous cannabinoids, anandamide (AEA) and 2-arachydonylglycerol (2-AG), reduce nociception in a variety of nociceptive assays, with no or minimal behavioral effects. In the present study we tested whether inhibition of these enzymes attenuates mechanical allodynia, and acetone-induced cold allodynia in mice subjected to chronic constriction injury of the sciatic nerve.

Minocycline treatment inhibits microglial activation and alters spinal levels of endocannabinoids in a rat model of neuropathic pain

Leonardo Guasti, Denise Richardson, Maulik JhaveriKhalil EldeebDavid BarrettMaurice R ElphickStephen PH AlexanderDavid KendallGregory J Michael and Victoria Chapman  (July 2009)

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Activation of spinal microglia contributes to aberrant pain responses associated with neuropathic pain states. Endocannabinoids (ECs) are present in the spinal cord, and inhibit nociceptive processing; levels of ECs may be altered by microglia which modulate the turnover of endocannabinoids in vitro. Here, we investigate the effect of minocycline, an inhibitor of activated microglia, on levels of the endocannabinoids anandamide and 2-arachidonoylglycerol (2-AG), and the related compound N-palmitoylethanolamine (PEA), in neuropathic spinal cord. Selective spinal nerve ligation (SNL) in rats resulted in mechanical allodynia and the presence of activated microglia in the ipsilateral spinal cord.