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

Abstract

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.

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

“…Previous studies have shown that intraperitoneal, intracerebral injection, or peroral administration of NB001 reduces pain-related behavioral responses in rodents with neuropathic or inflammatory pain. 17 , 34 , 35 In our present study, peroral administration of NB001 in chickens also significantly reduced spontaneous pain behaviors and mechanical hypersensitivity in gouty pain chickens. These data show that the peroral administration of NB001 has a good therapeutic effect on gouty pain.…”

“…Furthermore, we also found that NB001 had an analgesic effect on both male and female chickens, which is consistent with our one recent study in that we found NB001 showed an analgesic effect in female mice. 35 …”

Synaptic potentiation of anterior cingulate cortex contributes to chronic pain of Parkinson’s disease

“…As a novel target for chronic pain, adenylyl cyclase 1 (AC1) is essential for the presynaptic enhancement of glutamate release and the postsynaptic potentiation [ 12 , 41 ]. Moreover, the AC1 inhibitor, NB001, produces powerful analgesic effects in different animal models of chronic pain [ 21 , 42 ]. Our current findings strongly suggest that the AC1 inhibitor NB001 maybe used for the future treatment of chronic pain in PD patients.…”

“…Activity time, standing time and hanging time were recorded and analyzed. During 24 h recording, mice were housed in standard cages on a 12 h light/dark cycle with food and water provided ad libitum [ 21 ].…”

Evaluation of calcium-sensitive adenylyl cyclase AC1 and AC8 mRNA expression in the anterior cingulate cortex of mice with spared nerve injury neuropathy

“…In line with this neuron-specific expression, these ACs play specialized roles in synaptic plasticity in the spinal cord and brain of rodents ( Wang et al, 2011 , Griggs et al, 2019 ) where they augment NMDAR currents upstream of PKA phosphorylation of these channels ( Liauw et al, 2005 , Wang and Zhang, 2012 ). Genetic knockout of AC1 in mice demonstrates an important role for the Adcy1 gene in chronic hypernociception that occurs after nerve injury or other injuries ( Vadakkan et al, 2006 , Xu et al, 2008 , Wang et al, 2011 , Corder et al, 2013 , Griggs et al, 2019 , Zhou et al, 2021 ). Genetic knockout of Adcy8 suggests a specialized role for this enzyme in anxiety-like behavior in mice ( Bernabucci and Zhuo, 2016 ) but does not support a role in mechanical hypersensitivity after inflammation, although formalin nocifensive behavioral responses are attenuated in mice lacking the Adcy8 gene ( Wei et al, 2002 ).…”