Peripheral versus central mechanisms of the cannabinoid type 2 receptor agonist AM1710 in a mouse model of neuropathic pain

Wilkerson, Jenny L.; Alberti, Lauren B.; Kerwin, Audra A.; Ledent, Catherine; Thakur, Ganesh A.; Makriyannis, Alexandros; Milligan, Erin D.

doi:10.1002/brb3.1850

Cited by 11 publications

(6 citation statements)

References 82 publications

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“…In the present study it has been shown that intrathecal delivery of both THC and CBD reduce mechanical and cold allodynia in a nerve injury induced neuropathic pain model. While this is the first study to examine the spinal anti-allodynic actions of the phytocannabinoids THC and CBD, these anti-allodynic actions are consistent with those previously reported for synthetic cannabinoid receptors agonists and dihydroxyl phytocannabinoid analogues in a range of neuropathic pain models [ 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 ].…”

Section: Discussionsupporting

confidence: 86%

“…Another approach to lessening the side-effects associated with cannabinoids is to use site-directed drug delivery. Several studies have demonstrated that intrathecal delivery of synthetic cannabinoid CB1 and CB2 receptor agonists reduces allodynia in a range of neuropathic pain models of nerve injury, chemotherapeutic drugs, diabetes and cancer [ 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 ]. Surprisingly, relatively little is known about the intrathecal effects of the cannabis constituents, THC and CBD, in neuropathic pain models [ 35 , 36 ].…”

Section: Introductionmentioning

confidence: 99%

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Intrathecal Actions of the Cannabis Constituents Δ(9)-Tetrahydrocannabinol and Cannabidiol in a Mouse Neuropathic Pain Model

Casey

Mitchell

Sokolaj

et al. 2022

IJMS

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(1) Background: The psychoactive and non-psychoactive constituents of cannabis, Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), synergistically reduce allodynia in various animal models of neuropathic pain. Unfortunately, THC-containing drugs also produce substantial side-effects when administered systemically. We examined the effectiveness of targeted spinal delivery of these cannabis constituents, alone and in combination. (2) Methods: The effect of acute intrathecal drug delivery on allodynia and common cannabinoid-like side-effects was examined in a mouse chronic constriction injury (CCI) model of neuropathic pain. (3) Results: intrathecal THC and CBD produced dose-dependent reductions in mechanical and cold allodynia. In a 1:1 combination, they synergistically reduced mechanical and cold allodynia, with a two-fold increase in potency compared to their predicted additive effect. Neither THC, CBD nor combination THC:CBD produced any cannabis-like side-effects at equivalent doses. The anti-allodynic effects of THC were abolished and partly reduced by cannabinoid CB1 and CB2 receptor antagonists AM281 and AM630, respectively. The anti-allodynic effects of CBD were partly reduced by AM630. (4) Conclusions: these findings indicate that intrathecal THC and CBD, individually and in combination, could provide a safe and effective treatment for nerve injury induced neuropathic pain.

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Section: Discussionsupporting

confidence: 86%

Section: Introductionmentioning

confidence: 99%

Intrathecal Actions of the Cannabis Constituents Δ(9)-Tetrahydrocannabinol and Cannabidiol in a Mouse Neuropathic Pain Model

Casey

Mitchell

Sokolaj

et al. 2022

IJMS

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“…MCP-1 was decreased at 30 minutes within the dorsal horn of the spinal cord after i.p injection of AM1710 in the CCI model, indicating it is an early modulator in the mechanisms of reversal of neuropathic pain. 94 The increase in the TNF-α mRNA level observed here in the lumbar spinal cord after intraplantar AM1710 compared with vehicle treatment was unexpected and may reflect compensatory changes. More work is needed to better understand the role of TNF-α in the antiallodynic effects by CB 2 agonists and how CB 2 agonists impact the time course of changes in cytokines and chemokines during the development and maintenance of CIPN.…”

Section: Discussionmentioning

confidence: 67%

“…11 Antiallodynic effects of AM1710 cannot be attributed to CB 1 mechanisms. 21,73,77,94 Third, local hind paw injection of AM1710 reversed paclitaxel-induced allodynia in CB 2 EGFP but not CB 2 KO mice without producing antinociception in cremophor vehicle–treated mice. Intraplantar AM1710 was unlikely to act systemically (or in the CNS) as unilateral hind paw injection did not alter responsiveness of the hypersensitive paw contralateral to AM1710 injection.…”

Section: Discussionmentioning

confidence: 99%

A peripheral CB2 cannabinoid receptor mechanism suppresses chemotherapy-induced peripheral neuropathy: evidence from a CB2 reporter mouse

Lin

Carey

et al. 2021

Pain

Self Cite

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CB 2 cannabinoid receptors (CB 2 ) are a promising therapeutic target that lacks unwanted side effects of CB 1 activation. However, the cell types expressing CB 2 that mediate these effects remain poorly understood. We used transgenic mice with CB 2 promoter-driven expression of enhanced green fluorescent protein (EGFP) to study cell types that express CB 2 and suppress neuropathic nociception in a mouse model of chemotherapy-induced peripheral neuropathy. Structurally distinct CB 2 agonists (AM1710 and LY2828360) suppressed paclitaxel-induced mechanical and cold allodynia in CB 2 EGFP reporter mice with established neuropathy. Antiallodynic effects of AM1710 were blocked by SR144528, a CB 2 antagonist with limited CNS penetration. Intraplantar AM1710 administration suppressed paclitaxel-induced neuropathic nociception in CB 2 EGFP but not CB 2 knockout mice, consistent with a local site of antiallodynic action. mRNA expression levels of the anti-inflammatory cytokine interleukin-10 were elevated in the lumbar spinal cord after intraplantar AM1710 injection along with the proinflammatory cytokine tumor necrosis factor alpha and chemokine monocyte chemoattractant protein-1. CB 2 EGFP , but not wildtype mice, exhibited anti-GFP immunoreactivity in the spleen. However, the anti-GFP signal was below the threshold for detection in the spinal cord and brain of either vehicle-treated or paclitaxel-treated CB 2 EGFP mice. EGFP fluorescence was coexpressed with CB 2 immunolabeling in stratified patterns among epidermal keratinocytes. EGFP fluorescence was also expressed in dendritic cells in the dermis, Langerhans cells in the epidermis, and Merkel cells. Quantification of the EGFP signal revealed that Langerhans cells were dynamically increased in the epidermis after paclitaxel treatment. Our studies implicate CB 2 expressed in previously unrecognized populations of skin cells as a potential target for suppressing chemotherapy-induced neuropathic nociception.

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“…Contralateral changes may develop after unilateral CCI of the sciatic nerve, including spontaneous pain and mechanical hypersensitivity in hind paws (Paulson et al, 2002; Wilkerson et al, 2020), as well as gene expression in the spinal cord and DRGs (Jancalek et al, 2010). Because transcriptional changes in contralateral DRGs may differ from those on the ipsilateral side, we performed bilateral sciatic CCI to allow pooling of bilateral DRG tissues for sequencing and to avoid sample variations.…”

Section: Methodsmentioning

confidence: 99%

scRNA-sequencing reveals subtype-specific transcriptomic perturbations in DRG neurons ofPirt-EGFPfmice in neuropathic pain condition

Zhang

et al. 2022

Preprint

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Functionally distinct subtypes/clusters of dorsal root ganglion (DRG) neurons, which differ in soma size and neurochemical properties, may play different roles in nerve regeneration and pain. However, details about transcriptomic changes in different neuronal subtypes under maladaptive neuropathic pain conditions remain unclear. Chronic constriction injury (CCI) of the sciatic nerve represents a well-established model of neuropathic pain that mimics the etiology of clinical conditions. Therefore, we conducted single-cell RNA-sequencing (scRNA-seq) to characterize subtype-specific perturbations of transcriptomes in lumbar DRG neurons 7 days after sciatic CCI. By using Pirt-EGFPf mice that selectively express enhanced green fluorescent protein in DRG neurons, we established a highly efficient purification process to enrich neurons for scRNA-seq. We observed a loss of marker genes in injured neurons of 12 standard neuronal clusters, and the emergence of four prominent CCI-induced clusters at this peak-maintenance phase of neuropathic pain. Importantly, a portion of injured neurons from a subset of the 12 standard clusters (NP1, PEP5, NF1, and NF2) were spared from injury-induced identity loss, suggesting subtype-specific transcriptomic changes in injured neurons. Moreover, uninjured neurons, which are necessary for mediating the evoked pain, also demonstrated subtype-specific transcriptomic perturbations in these clusters, but not others. Notably, male and female mice showed differential transcriptomic changes in multiple neuronal clusters after CCI, suggesting transcriptomic sexual dimorphism in primary sensory neurons after nerve injury. Collectively, these findings may contribute to the identification of new target genes and development of DRG neuron subtype-specific therapies for optimizing neuropathic pain treatment and nerve regeneration.

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Peripheral versus central mechanisms of the cannabinoid type 2 receptor agonist AM1710 in a mouse model of neuropathic pain

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 11 publications

References 82 publications

Intrathecal Actions of the Cannabis Constituents Δ(9)-Tetrahydrocannabinol and Cannabidiol in a Mouse Neuropathic Pain Model

Intrathecal Actions of the Cannabis Constituents Δ(9)-Tetrahydrocannabinol and Cannabidiol in a Mouse Neuropathic Pain Model

A peripheral CB2 cannabinoid receptor mechanism suppresses chemotherapy-induced peripheral neuropathy: evidence from a CB2 reporter mouse

scRNA-sequencing reveals subtype-specific transcriptomic perturbations in DRG neurons ofPirt-EGFPfmice in neuropathic pain condition

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