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

ABSTRACT: The CB₂ R agonist AM1710, examined in animal models of peripheral neuropathy, is effective in controlling aberrant light touch sensitivity, referred to as mechanical allodynia. However, nonspecific binding of AM1710 to CB₁ R, either peripherally or centrally, could be partially responsible for the analgesic effects of AM1710. Thus, we sought to determine in mice whether spinal (intrathecal; i.t.) or peripheral AM1710 administration could lead to anti-allodynia by reducing the protein expression of spinal and dorsal root ganglia (DRG) proinflammatory cytokines and elevating the anti-inflammatory cytokine interleukin-10 (IL-10) in the absence of CB₁ R. Macrophage cell cultures were examined to characterize AM1710-mediated suppression of the proinflammatory cytokine tumor necrosis factor-alpha (TNF-?). Either i.p. or i.t. AM1710 reversed CCI-induced mechanical allodynia to sham levels in CB₁ R (-/-), (+/-), (+/+) mice. CCI-induced neuropathy decreased IL-10 immunoreactivity (IR) in the dorsal root ganglia (DRG) and the dorsal horn of the spinal cord, with i.t. AM1710 restoring basal IL-10 IR. CCI-induced elevations in proinflammatory cytokine IR were decreased within the spinal cord only after i.t. AM1710 in all mouse genotypes. Meanwhile, within DRG tissue from neuropathic mice, proinflammatory cytokines were decreased following either i.p. or i.t. AM1710. Analysis of cultured supernatants revealed AM1710 decreased TNF-alpha protein. We conclude that CB₁ R is dispensable for either peripheral or central anti-allodynic actions of AM1710 in neuropathic mice. Cannabinoid CB₂ R agonists produce heightened spinal IL-10 which may be clinically relevant to successfully treat neuropathic pain.

SUBMITTER: Wilkerson JL

PROVIDER: S-EPMC7749576 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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

Wilkerson Jenny L JL Alberti Lauren B LB Kerwin Audra A AA Ledent Catherine A CA Thakur Ganesh A GA Makriyannis Alexandros A Milligan Erin D ED

Brain and behavior 20200925 12

The CB<sub>2</sub> R agonist AM1710, examined in animal models of peripheral neuropathy, is effective in controlling aberrant light touch sensitivity, referred to as mechanical allodynia. However, nonspecific binding of AM1710 to CB<sub>1</sub> R, either peripherally or centrally, could be partially responsible for the analgesic effects of AM1710. Thus, we sought to determine in mice whether spinal (intrathecal; i.t.) or peripheral AM1710 administration could lead to anti-allodynia by reducing t ...[more]

PMID: 32977358

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Project description:PURPOSE:This is a comprehensive review of the current literature on central neuropathic pain mechanisms that is secondary to spinal cord injury. It reviews recent and seminal findings on the pathophysiology, diagnosis, and treatment and compares treatment options and recommendations. RECENT FINDINGS:Neuropathic pain (NP) is a common complication of spinal cord injury (SCI). Chronicity of NP is attributed to increased abundance of inflammatory mediators and ion channel dysfunction leading to afferent nerve sensitization; nerve damage and nerve-glia cross talk have also been implicated. Conventional treatment is medical and has had limited success. Recent studies have made headway in identifying novel biomarkers, including microRNA and psychosocial attributes that can predict progress from SCI to chronic NP (CNP). Recent advances have provided evidence of efficacy for two promising drugs. Baclofen was able to provide good, long-lasting pain relief. Ziconotide, a voltage-gated calcium channel blocker, was studied in a small trial and was able to provide good analgesia in most participants. However, several participants had to be withdrawn because of worrisome creatine phosphokinase (CPK) elevations, and further studies are required to define its safety profile. Non-medical interventions include brain sensitization and biofeedback techniques. These methods have recently had encouraging results, albeit preliminary. Case reports of non-conventional techniques, such as hypnosis, were also reported. CNP is a common complication of SCI and is a prevalent disorder with significant morbidity and disability. Conventional medical treatment is limited in efficacy. Recent studies identified baclofen and ziconotide as possible new therapies, alongside non-medical interventions. Further research into the pathophysiology is required to identify further therapy candidates. A multidisciplinary approach, including psychosocial support, medical and non-medical interventions, is likely needed to achieve therapeutic effects in this difficult to treat syndrome.

Dataset Information

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

Publications

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

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