Neuronal Adenylyl Cyclase Targeting Central Plasticity for the Treatment of Chronic Pain

Li, Xu Hui; Chen, Qi-Yu; Zhuo, Min

doi:10.1007/s13311-020-00927-1

Cited by 23 publications

(20 citation statements)

References 78 publications

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“…Rodent studies have shown that calcium-stimulated AC1 is essential for central synaptic plasticity, such as NMDAR-dependent LTP, which is a key cellar mechanism for chronic pain. 11 , 12 Our unpublished data also show that there is LTP in the dorsolateral corticoid area of chicken, which is similar to the functional area of anterior cingulate cortex in rodents and humans. 29 , 30 Taken together, these results indicate that AC1 signaling pathway regulates gouty pain in chickens potentially possessed the same mechanism as in rodents.…”

Section: Discussionsupporting

confidence: 59%

Selective inhibition of adenylyl cyclase subtype 1 reduces inflammatory pain in chicken of gouty arthritis

Liu

Shi

Zhang³

et al. 2021

Mol Pain

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Lack of uricase leads to the high incidence of gout in humans and poultry, which is different from rodents. Therefore, chicken is considered to be one of the ideal animal models for the study of gout. Gout-related pain caused by the accumulation of urate in joints is one type of inflammatory pain, which causes damage to joint function. Our previous studies have demonstrated the crucial role of calcium-stimulated adenylyl cyclase subtype 1 (AC1) in inflammatory pain in rodents; however, there is no study in poultry. In the present study, we injected mono-sodium urate (MSU) into the left ankle joint of the chicken to establish a gouty arthritis model, and tested the effect of AC1 inhibitor NB001 on gouty arthritis in chickens. We found that MSU successfully induced spontaneous pain behaviors including sitting, standing on one leg, and limping after 1–3 h of injection into the left ankle of chickens. In addition, edema and mechanical pain hypersensitivity also occurred in the left ankle of chickens with gouty arthritis. After peroral administration of NB001 on chickens with gouty arthritis, both the spontaneous pain behaviors and the mechanical pain hypersensitivity were effectively relieved. The MSU-induced edema in the left ankle of chickens was not affected by NB001, suggesting a central effect of NB001. Our results provide a strong evidence that AC1 is involved in the regulation of inflammatory pain in poultry. A selective AC1 inhibitor NB001 produces an analgesic effect (not anti-inflammatory effect) on gouty pain and may be used for future treatment of gouty pain in both humans and poultry.

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Section: Discussionsupporting

confidence: 59%

Selective inhibition of adenylyl cyclase subtype 1 reduces inflammatory pain in chicken of gouty arthritis

Liu

Shi

Zhang³

et al. 2021

Mol Pain

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“…Moreover, L-VGCC and mGluRs were required for BDNF induced synaptic enhancement. AC1 was considered critical for TBS produced synaptic enhancement in the ACC 29 , we also found that BDNF produced enhancement was blocked in genetic deletion of AC1 or by a selective AC1 inhibitor NB001. These results provided strong evidence that ACC synaptic transmission might through AC1 signal pathway, although the exact signaling pathway remains to be determined.…”

Section: Mechanisms Of Acc Bdnf Induced Synaptic Enhancementsupporting

confidence: 61%

Brain-Derived Neurotrophic Factor Produced Long-Term Synaptic Enhancement in The Anterior Cingulate Cortex of Adult Mice

Miao

Pan

et al. 2021

Preprint

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Previous studies show that brain-derived neurotrophic factor (BDNF) is one of diffusible messengers for enhancing synaptic transmission in the hippocampus. Less information is available for possible roles of BDNF in the anterior cingulate cortex (ACC). In the present study, we used 64-electrode array field recording system to investigate the effect of BDNF on ACC excitatory transmission. We found that BDNF enhanced synaptic responses in a dose-dependently manner in the ACC. The enhancement was long-lasting, and persisted for at least three hours. In addition to the enhancement, BDNF also recruited inactive synaptic responses in the ACC. Bath application of the tropomyosin receptor kinase B (TrkB) receptor antagonist K252a blocked BDNF-induced enhancement. L-type voltage-gated calcium channels (L-VGCC), metabotropic glutamate receptors (mGluRs), but not NMDA receptors were required for BDNF-produced enhancement. Moreover, calcium-stimulated adenylyl cyclase subtype 1 (AC1) but not AC8 was essential for the enhancement. A selective AC1 inhibitor NB001 completely blocked the enhancement. Furthermore, BDNF-produced enhancement occluded theta burst stimulation (TBS) induced long-term potentiation (LTP), suggesting that they may share similar signaling mechanisms. Finally, the expression of BDNF-induced enhancement depends on postsynaptic incorporation of calcium-permeable AMPA receptors (CP-AMPARs) and protein kinase Mζ (PKMζ). Our results demonstrate that cortical BDNF may contribute to synaptic potentiation in the ACC.

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“…In summary, we provide strong evidence that NB001 is a potential drug for the treatment of chronic pain in both male and females. 14 , 36 …”

Section: Discussionmentioning

confidence: 99%

Inhibition of calcium-stimulated adenylyl cyclase subtype 1 (AC1) for the treatment of neuropathic and inflammatory pain in adult female mice

et al. 2021

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Cortical long-term potentiation (LTP) serves as a cellular model for chronic pain. As an important subtype of adenylyl cyclases (ACs), adenylyl cyclase subtype 1 (AC1) is critical for the induction of cortical LTP in the anterior cingulate cortex (ACC). Genetic deletion of AC1 or pharmacological inhibition of AC1 blocked behavioral allodynia in animal models of neuropathic and inflammatory pain. Our previous experiments have identified a lead candidate AC1 inhibitor, NB001, which is highly selective for AC1 over other AC isoforms, and found that NB001 is effective in inhibiting behavioral allodynia in animal models of chronic neuropathic and inflammatory pain. However, previous experiments were carried out in adult male animals. Considering the potential gender difference as an important issue in researches of pain and analgesia, we investigated the effect of NB001 in female chronic pain animal models. We found that NB001, when administered orally, has an analgesic effect in female animal models of neuropathic and inflammatory pain without any observable side effect. Genetic deletion of AC1 also reduced allodynia responses in models of neuropathic pain and chronic inflammation pain in adult female mice. In brain slices of adult female mice, bath application of NB001(20 μM) blocked the induction of LTP in ACC. Our results indicate that calcium-stimulated AC1 is required for injury-related cortical LTP and behavioral allodynia in both sexes of adult animals, and NB001 can be used as a potential therapeutic drug for treating neuropathic and inflammatory pain in man and woman.

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Neuronal Adenylyl Cyclase Targeting Central Plasticity for the Treatment of Chronic Pain

Cited by 23 publications

References 78 publications

Selective inhibition of adenylyl cyclase subtype 1 reduces inflammatory pain in chicken of gouty arthritis

Selective inhibition of adenylyl cyclase subtype 1 reduces inflammatory pain in chicken of gouty arthritis

Brain-Derived Neurotrophic Factor Produced Long-Term Synaptic Enhancement in The Anterior Cingulate Cortex of Adult Mice

Inhibition of calcium-stimulated adenylyl cyclase subtype 1 (AC1) for the treatment of neuropathic and inflammatory pain in adult female mice

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