The central cannabinoid receptor type-2 (CB2) and chronic pain

Shang, Yu-chao; Tang, Yuying

doi:10.1080/00207454.2016.1257992

Cited by 33 publications

(27 citation statements)

References 112 publications

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“…Both CB1 and CB2 receptor agonists demonstrate anti-nociceptive activity, whether used singly or in combination, with CB2 activity believed to affect microglial cells and thereby reduce neuro-inflammatory mechanisms [ 34 , 35 ]. The CB2 receptor is thought to be particularly important in central neuronal pain circuits, as agonist activity induces dopamine release in mid-brain areas, contributing to descending pain control and the placebo effect [ 36 ]. Inflammatory effects can either be modulated via the upregulation of cannabinoid receptor activity or increased production of endocannabinoids, providing an attenuation in joint destruction in preclinical models of inflammatory arthritis that mimic human rheumatoid arthritis [ 30 , 32 ].…”

Section: Role Of Cannabinoids In Inflammation and Painmentioning

confidence: 99%

Cannabinoid Delivery Systems for Pain and Inflammation Treatment

Bruni¹,

et al. 2018

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There is a growing body of evidence to suggest that cannabinoids are beneficial for a range of clinical conditions, including pain, inflammation, epilepsy, sleep disorders, the symptoms of multiple sclerosis, anorexia, schizophrenia and other conditions. The transformation of cannabinoids from herbal preparations into highly regulated prescription drugs is therefore progressing rapidly. The development of such drugs requires well-controlled clinical trials to be carried out in order to objectively establish therapeutic efficacy, dose ranges and safety. The low oral bioavailability of cannabinoids has led to feasible methods of administration, such as the transdermal route, intranasal administration and transmucosal adsorption, being proposed. The highly lipophilic nature of cannabinoids means that they are seen as suitable candidates for advanced nanosized drug delivery systems, which can be applied via a range of routes. Nanotechnology-based drug delivery strategies have flourished in several therapeutic fields in recent years and numerous drugs have reached the market. This review explores the most recent developments, from preclinical to advanced clinical trials, in the cannabinoid delivery field, and focuses particularly on pain and inflammation treatment. Likely future directions are also considered and reported.

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Section: Role Of Cannabinoids In Inflammation and Painmentioning

confidence: 99%

Cannabinoid Delivery Systems for Pain and Inflammation Treatment

Bruni¹,

et al. 2018

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“…199 CB2 receptor antagonists may be a potential target in treating chronic pain of several etiologies by modifying cytokine profile when blocking peripheral immune tissue receptors, and by blocking receptors in neurons and glial cells. 200 …”

Section: Survey Of Current Targets Of Pain Therapeuticsmentioning

confidence: 99%

Basic/Translational Development of Forthcoming Opioid- and Nonopioid-Targeted Pain Therapeutics

Knezevic

Yekkirala

Yaksh

2017

Anesthesia &Amp; Analgesia

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Opioids Opioids represent an efficacious therapeutic modality for some, but not all pain states. Singular reliance on opioid therapy for pain management, has limitations and abuse potential has deleterious consequences for patient and society. Our understanding of pain biology has yielded insights and opportunities for alternatives to conventional opioid agonists. The aim is to have efficacious therapies, with acceptable side effect profiles and minimal abuse potential, which is to say an absence of re-enforcing activity in the absence of a pain state. The present work provides a non-exclusive overview of current drug targets and potential future directions of research and development. We discuss channels activators and blockers, including: sodium channel blockers, potassium channel activators and calcium channel blockers; glutamate receptor targeted agents, including: NMDA, AMPA and metabotropic receptors). Further, we discuss therapeutics targeted at GABA, alpha2 adrenergic and opioid receptors. We also considered antagonists of angiotensin 2 and Toll receptors, and agonists/antagonists of adenosine, purine receptors. And cannabinoids. Novel targets considered are those focusing on lipid mediators and anti-inflammatory cytokines. Of interest is development of novel targeting strategies which produce long-term alterations in pain signaling, including viral transfection and toxins. We consider issues in the development of drugable molecules, including preclinical screening. While there are examples of successful translation, mechanistically promising pre-clinical candidates may unexpectedly fail during clinical trials because the preclinical models may not recapitulate the particular human pain condition being addressed. Molecular target characterization can diminish the disconnect between preclinical and humans’ targets, which should assist in developing non-addictive analgesics.

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“…Cannabinoid CB2 receptor (CB2r) agonists show efficacy in animal models of chronic inflammatory and neuropathic pain, suggesting that they may be effective inhibitors of persistent pain in humans (Bie et al, 2018; Maldonado et al, 2016; Shang and Tang, 2017). However, many preclinical studies assess reflexive-defensive reactions to evoked nociceptive stimuli and fail to take into account spontaneous pain, one of the most prevalent symptoms of chronic pain conditions in humans (Backonja and Stacey, 2004; Mogil et al, 2010; Rice et al, 2018) that triggers coping responses such as painkiller consumption.…”

Section: Introductionmentioning

confidence: 99%

“…CB2r, the main cannabinoid receptors in peripheral immune cells (Fernández-Ruiz et al, 2007; Schmöle et al, 2015a), are found in monocytes, macrophages and lymphocytes, and their expression increases in conditions of active inflammation (Schmöle et al, 2015b; Shang and Tang, 2017). The presence of CB2r in the nervous system was thought to be restricted to microglia and limited to pathological conditions or intense neuronal activity (Manzanares et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Protective role of neuronal and lymphoid cannabinoid CB2 receptors in neuropathic pain

Cabañero

Ramírez-López

Drews

et al. 2020

Preprint

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1Cannabinoid CB2 receptor (CB2r) agonists are potential painkillers void of 2 psychotropic effects. Peripheral immune cells, neurons and glia express CB2r, 3 however the involvement of CB2r from these cells in neuropathic pain remains 4 unresolved. We explored spontaneous neuropathic pain through on-demand self-5 administration of the selective CB2r agonist JWH133 in wild-type and knockout mice 6 lacking CB2r in neurons, monocytes or constitutively. Operant self-administration 7 reflected drug-taking to alleviate spontaneous pain, nociceptive and affective 8 manifestations. While constitutive deletion of CB2r disrupted JWH133-taking 9 behavior, this behavior was not modified in monocyte-specific CB2r knockouts and 10 was increased in mice defective in neuronal CB2r knockouts suggestive of increased 11 spontaneous pain. Interestingly, CB2r-positive lymphocytes infiltrated the injured 12 nerve and possible CB2r transfer from immune cells to neurons was found. 13 Lymphocyte CB2r depletion also exacerbated JWH133 self-administration and 14 inhibited antinociception. This work identifies a simultaneous activity of neuronal and 15 lymphoid CB2r that protects against spontaneous and evoked neuropathic pain. 16 3 Introduction 17Cannabinoid CB2 receptor (CB2r) agonists show efficacy in animal models of 18 chronic inflammatory and neuropathic pain, suggesting that they may be effective 19 inhibitors of persistent pain in humans (Bie et al., 2018; Maldonado et al., 2016; 20 Shang and Tang, 2017). However, many preclinical studies assess reflexive-21 defensive reactions to evoked nociceptive stimuli and fail to take into account 22 spontaneous pain, one of the most prevalent symptoms of chronic pain conditions in 23 humans (Backonja and Stacey, 2004; Mogil et al., 2010; Rice et al., 2018) that 24 triggers coping responses such as painkiller consumption. As a consequence, 25 conclusions drawn from animal models relying on evoked nociception may not 26 translate into efficient pharmacotherapy in humans (Huang et al., 2018; Mogil, 2009; 27 Percie du Sert and Rice, 2014), which underlines the need to apply more 28 sophisticated animal models with clear translational value. Operant paradigms in 29 which animals voluntarily self-administer analgesic compounds can provide high 30 translatability and also identify in the same experimental approach potential 31 addictive properties of the drugs (Mogil, 2009; Mogil et al., 2010; O'Connor et al., 32 2011). In this line, a previous work using a CB2r agonist, AM1241, showed drug-33 taking behavior in nerve-injured rats and not in sham-operated animals, suggesting 34 spontaneous pain relief and lack of abuse potential of CB2r agonists (Gutierrez et 35 al., 2011), although the possible cell populations and mechanisms involved remain36unknown. In addition, a recent multicenter study demonstrated off-target effects of 37 this compound on anandamide reuptake, calcium channels and serotonin, histamine 38 and kappa opioid receptors (Soethoudt et al., 2017).CB2r, the main ca...

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The central cannabinoid receptor type-2 (CB2) and chronic pain

Cited by 33 publications

References 112 publications

Cannabinoid Delivery Systems for Pain and Inflammation Treatment

Cannabinoid Delivery Systems for Pain and Inflammation Treatment

Basic/Translational Development of Forthcoming Opioid- and Nonopioid-Targeted Pain Therapeutics

Protective role of neuronal and lymphoid cannabinoid CB2 receptors in neuropathic pain

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