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

2021 ◽  
Vol 17 ◽  
pp. 174480692110216
Author(s):  
Zhaoxiang Zhou ◽  
Wantong Shi ◽  
Kexin Fan ◽  
Man Xue ◽  
Sibo Zhou ◽  
...  
Keyword(s):  
Chronic Pain ◽  
Animal Models ◽  
Adenylyl Cyclase ◽  
Adult Female ◽  
Inflammatory Pain ◽  
Long Term Potentiation ◽  
Anterior Cingulate ◽  
Therapeutic Drug ◽  
Female Mice ◽  
Genetic Deletion

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.

scholarly journals Optimization of a Pyrimidinone Series for Selective Inhibition of Ca2+/Calmodulin-Stimulated Adenylyl Cyclase 1 Activity for the Treatment of Chronic Pain

2021 ◽  
Author(s):  
Jason Scott ◽  
Monica Soto-Velasquez ◽  
Michael Hayes ◽  
Justin Lavigne ◽  
Heath Miller ◽  
...  
Keyword(s):  
Chronic Pain ◽  
Physicochemical Properties ◽  
Adenylyl Cyclase ◽  
Learning And Memory ◽  
Inflammatory Pain ◽  
Selective Inhibition ◽  
Behavioral Studies ◽  
Morphine Administration ◽  
Ic50 Values ◽  
Pain Sensitization

Adenylyl cyclase type 1 is an emerging target for the treatment of chronic pain that is downstream on the analgesic pathway from the traditional µ-opioid receptor. AC1 is expressed in the central nervous system and critical for signaling in pain sensitization. Behavioral studies have revealed AC1 knockout mice exhibit reduced behavioral pain sensitization responses similar to morphine administration. AC1, and a closely related isoform AC8, are also implicated to have a role in learning and memory signaling processes. However, reports suggest selectively targeting AC1 over AC8 may be a viable strategy to eliminate potential deleterious effects on learning and memory. Our team has carried out cellular screening for inhibitors of AC1 that yielded a pyrazolyl-pyrimidinone scaffold with potency comparable to previously published AC1 inhibitors, selectivity versus AC8, and improved drug-like physicochemical properties. Structure-activity relationship (SAR) studies produced 36 analogs that balanced improvements in potency with cellular IC50 values as low as 0.25 µM and selectivity versus AC8. Prioritized analogs were selective for AC1 compared to other AC isoforms and other common neurological targets. A representative analog was assessed for efficacy in a mouse model of inflammatory pain and displayed modest anti-allodynic effects. This series of compounds represents the most potent and selective inhibitors of Ca2+/Calmodulin-stimulated AC1 activity to date with reduced off-target liabilities and improved drug-like physicochemical properties making them promising lead compounds for the treatment of inflammatory pain.

Sympathetic component of neuropathic pain: Animal models and clinical diagnosis

1997 ◽  
Vol 20 (3) ◽  
pp. 468-469
Author(s):  
Laszlo A. Urban
Keyword(s):  
Experimental Data ◽  
Chronic Pain ◽  
Neuropathic Pain ◽  
Animal Models ◽  
Clinical Diagnosis ◽  
Inflammatory Pain ◽  
Ongoing Debate ◽  
Pain Syndromes ◽  
Sympathetic Nervous

Although clinical studies and animal models seem to establish an important role for the sympathetic nervous system in many forms of neuropathic and inflammatory pain, there is an ongoing debate on the classification of pain syndromes with sympathetic components. The confusion originates from several sources: failure to acknowledge that the pathomechanism of chronic pain can change during the progress of the disease, which is now strongly underlined by experimental data from suitable animal models. Neuropathic pain is a vaguely defined collection of pain syndromes which includes painful conditions with diverse and largely unknown patho-mechanisms. Clinical diagnosis is difficult and well designed, placebo controlled sympathectomy is rarely performed. [blumberg et al.]

scholarly journals GPR171 Agonist Reduces Chronic Neuropathic and Inflammatory Pain in Male, but not in Female Mice

2021 ◽  
Author(s):  
Akila Ram ◽  
Taylor Edwards ◽  
Ashley McCarty ◽  
Leela Afrose ◽  
Max V McDermott ◽  
...  
Keyword(s):  
Chronic Pain ◽  
Neuropathic Pain ◽  
Inflammatory Pain ◽  
Therapeutic Potential ◽  
Periaqueductal Gray ◽  
Male Mice ◽  
Once Daily ◽  
Female Mice ◽  
Protein Levels ◽  
Thermal Hypersensitivity

Chronic pain is a growing public health crisis that requires exigent and efficacious therapeutics. GPR171 is a promising therapeutic target that is widely expressed through the brain, including within the descending pain modulatory regions. Here, we explore the therapeutic potential of the GPR171 agonist, MS15203, in its ability to alleviate chronic pain in male and female mice using a once-daily systemic dose (10mg/kg, i.p.) of MS15203 over the course of 5 days. We found that in our models of Complete Freunds Adjuvant (CFA)-induced inflammatory pain and chemotherapy-induced peripheral neuropathy (CIPN), MS15203 did not reduce thermal hypersensitivity and allodynia, respectively, in female mice. On the other hand, MS15203 treatment decreased the duration of thermal hypersensitivity in CFA-treated male mice following 3 days of once-daily administration. MS15203 treatment also produced an improvement in allodynia in male mice, but not female mice, in neuropathic pain after 5 days of treatment. Gene expression of GPR171 and that of its endogenous ligand BigLEN, encoded by the gene PCSK1N, were unaltered within the periaqueductal gray in both male and female mice following inflammatory and neuropathic pain. However, following neuropathic pain in male mice, the protein levels of GPR171 were decreased in the periaqueductal gray. Treatment with MS15203 then rescued the protein levels of GPR171 in the periaqueductal gray of these mice. Taken together, our results identify GPR171 as a GPCR that displays sexual dimorphism in alleviation of chronic pain. Further, our results suggest that GPR171 and MS15203 have demonstrable therapeutic potential in the treatment of chronic pain.

scholarly journals GPR171 Agonist Reduces Chronic Neuropathic and Inflammatory Pain in Male, But Not Female Mice

2021 ◽  
Vol 2 ◽  
Author(s):  
Akila Ram ◽  
Taylor Edwards ◽  
Ashley McCarty ◽  
Leela Afrose ◽  
Max V. McDermott ◽  
...  
Keyword(s):  
Chronic Pain ◽  
Neuropathic Pain ◽  
Inflammatory Pain ◽  
Therapeutic Potential ◽  
Male Mice ◽  
Once Daily ◽  
Male And Female ◽  
Female Mice ◽  
Protein Levels ◽  
Thermal Hypersensitivity

Chronic pain is a growing public health crisis that requires exigent and efficacious therapeutics. GPR171 is a promising therapeutic target that is widely expressed through the brain, including within the descending pain modulatory regions. Here, we explore the therapeutic potential of the GPR171 agonist, MS15203, in its ability to alleviate chronic pain in male and female mice using a once-daily systemic dose (10 mg/kg, i.p.) of MS15203 over the course of 5 days. We found that in our models of Complete Freund's Adjuvant (CFA)-induced inflammatory pain and chemotherapy-induced peripheral neuropathy (CIPN), MS15203 did not alleviate thermal hypersensitivity and allodynia, respectively, in female mice. On the other hand, MS15203 treatment decreased the duration of thermal hypersensitivity in CFA-treated male mice following 3 days of once-daily administration. MS15203 treatment also produced an improvement in allodynia in male mice, but not female mice, in neuropathic pain after 5 days of treatment. Gene expression of GPR171 and that of its endogenous ligand BigLEN, encoded by the gene PCSK1N, were unaltered within the periaqueductal gray (PAG) in both male and female mice following inflammatory and neuropathic pain. However, following neuropathic pain in male mice, the protein levels of GPR171 were decreased in the PAG. Treatment with MS15203 then rescued the protein levels of GPR171 in the PAG of these mice. Taken together, our results identify GPR171 as a GPCR that displays sexual dimorphism in alleviation of chronic pain. Further, our results suggest that GPR171 and MS15203 have demonstrable therapeutic potential in the treatment of chronic pain.

scholarly journals Long-term potentiation in the anterior cingulate cortex and chronic pain

2014 ◽  
Vol 369 (1633) ◽  
pp. 20130146 ◽  
Author(s):  
Min Zhuo
Keyword(s):  
Chronic Pain ◽  
Anterior Cingulate Cortex ◽  
Dorsal Horn ◽  
Glutamate Release ◽  
Cingulate Cortex ◽  
Long Term Potentiation ◽  
Anterior Cingulate ◽  
Spinal Cord Dorsal Horn ◽  
Term Potentiation

Glutamate is the primary excitatory transmitter of sensory transmission and perception in the central nervous system. Painful or noxious stimuli from the periphery ‘teach’ humans and animals to avoid potentially dangerous objects or environments, whereas tissue injury itself causes unnecessary chronic pain that can even last for long periods of time. Conventional pain medicines often fail to control chronic pain. Recent neurobiological studies suggest that synaptic plasticity taking place in sensory pathways, from spinal dorsal horn to cortical areas, contributes to chronic pain. Injuries trigger long-term potentiation of synaptic transmission in the spinal cord dorsal horn and anterior cingulate cortex, and such persistent potentiation does not require continuous neuronal activity from the periphery. At the synaptic level, potentiation of excitatory transmission caused by injuries may be mediated by the enhancement of glutamate release from presynaptic terminals and potentiated postsynaptic responses of AMPA receptors. Preventing, ‘erasing’ or reducing such potentiation may serve as a new mechanism to inhibit chronic pain in patients in the future.

scholarly journals The Effect of Electroacupuncture on PKMzeta in the ACC in Regulating Anxiety-Like Behaviors in Rats Experiencing Chronic Inflammatory Pain

2017 ◽  
Vol 2017 ◽  
pp. 1-13 ◽  
Author(s):  
Junying Du ◽  
Junfan Fang ◽  
Cun Wen ◽  
Xiaomei Shao ◽  
Yi Liang ◽  
...  
Keyword(s):  
Chronic Pain ◽  
Protein Expression ◽  
Inflammatory Pain ◽  
Direct Evidence ◽  
Anterior Cingulate ◽  
Model Group ◽  
Pain Model ◽  
Chronic Inflammatory Pain ◽  
Withdrawal Threshold ◽  
Other Substances

Chronic inflammatory pain can induce emotional diseases. Electroacupuncture (EA) has effects on chronic pain and pain-related anxiety. Protein kinase Mzeta (PKMzeta) has been proposed to be essential for the maintenance of pain and may interact with GluR1 to maintain CNS plasticity in the anterior cingulate cortex (ACC). We hypothesized that the PKMzeta-GluR1 pathway in the ACC may be involved in anxiety-like behaviors of chronic inflammatory pain and that the mechanism of EA regulation of pain emotion may involve the PKMzeta pathway in the ACC. Our results showed that chronic inflammatory pain model decreased the paw withdrawal threshold (PWT) and increased anxiety-like behaviors. The protein expression of PKCzeta, p-PKCzeta (T560), PKMzeta, p-PKMzeta (T560), and GluR1 in the ACC of the model group were remarkably enhanced. EA increased PWT and alleviated anxiety-like behaviors. EA significantly inhibited the protein expression of p-PKMzeta (T560) in the ACC, and only a downward trend effect for other substances. Further, the microinjection of ZIP remarkably reversed PWT and anxiety-like behaviors. The present study provides direct evidence that the PKCzeta/PKMzeta-GluR1 pathway is related to pain and pain-induced anxiety-like behaviors. EA treatment both increases pain-related somatosensory behavior and decreases pain-induced anxiety-like behaviors by suppressing PKMzeta activity in the ACC.

scholarly journals Preoperative anxiety induces chronic postoperative pain by activating astrocytes in the anterior cingulate cortex region

2019 ◽  
Vol 65 (9) ◽  
pp. 1174-1180 ◽  
Author(s):  
Damin Gu ◽  
Minmin Zhou ◽  
Chao Han ◽  
Daoyun Lei ◽  
Songhui Xie ◽  
...  
Keyword(s):  
Chronic Pain ◽  
Postoperative Pain ◽  
Anterior Cingulate Cortex ◽  
Cingulate Cortex ◽  
Long Term Potentiation ◽  
Preoperative Anxiety ◽  
Anterior Cingulate ◽  
Chronic Postoperative Pain ◽  
Term Potentiation ◽  
Mechanical Thresholds

SUMMARY OBJECTIVE The study aims to explore the relationship between preoperative anxiety and chronic postoperative pain. METHODS A total of forty rats were divided into four groups, control, single-prolonged stress alone, Hysterectomy alone, and SPS+ Hysterectomy. The paw withdrawal mechanical thresholds (PWMT) were examined. qRT-PCR and western blotting assay were performed to detect the GFAP expression in astrocytes isolated from the anterior cingulate cortex (ACC) region. In addition, the long-term potentiation (LTP) in ACC was examined. RESULTS Rats in the SPS group or the Hysterectomy alone group had no significant effect on chronic pain formation, but SPS can significantly induce chronic pain after surgery. Astrocytes were still active, and the LTP was significantly increased three days after modeling in the SPS+Hysterectomy group. CONCLUSIONS anxiety can induce chronic pain by activating astrocytes in the ACC region.

scholarly journals Reduced activity of Adenylyl Cyclase 1 Attenuates Morphine Induced Hyperalgesia and Inflammatory Pain in Mice

2020 ◽  
Author(s):  
Kayla Johnson ◽  
Alexis Doucette ◽  
Alexis Edwards ◽  
Val J. Watts ◽  
Amanda H. Klein
Keyword(s):  
Chronic Pain ◽  
Adenylyl Cyclase ◽  
Inflammatory Pain ◽  
Intrathecal Injection ◽  
Morphine Tolerance ◽  
Opioid Tolerance ◽  
Clinical Approach ◽  
Opioid Administration ◽  
Opioid Induced Hyperalgesia ◽  
Adenylyl Cyclase 1

AbstractOpioid tolerance and opioid-induced hyperalgesia during repeated opioid administration and chronic pain are associated with upregulation of adenylyl cyclase activity. The objective of this study was to test the hypothesis that a reduction in adenylyl cyclase 1 (AC1) activity or expression would attenuate morphine tolerance and hypersensitivity, and inflammatory pain using murine models. To investigate opioid tolerance and opioid-induced hyperalgesia, mice were subjected to twice daily treatments of saline or morphine using either a static (15 mg/kg, 5 days) or an escalating tolerance paradigm (10-40 mg/kg, 4 days). Systemic treatment with an AC1 inhibitor, ST03437 (5 mg/kg, ip), reduced morphine tolerance and morphine hyperalgesia in mice. Lumbar intrathecal administration of a vector incorporating adeno-associated virus and short-hairpin RNA against Adcy1 reduced morphine induced hypersensitivity compared to control vector treated mice. In contrast, morphine antinociception, along with baseline thermal paw withdrawal latencies, motor performance, exploration in an open field test, and burrowing behaviors were not affected by intrathecal Adcy1 knockdown. Knockdown of Adcy1 by intrathecal injection also attenuated inflammatory mechanical hyperalgesia after intraplantar administration of Complete Freund’s Adjuvant (CFA) after one week post injection. This Adcy1 knockdown strategy also increased burrowing and nesting activity after CFA injection when compared to controls. Together, these data indicate targeting AC1 to mitigate opioid-induced adverse effects, or as a method to treat chronic pain, are appropriate as a clinical approach and further development into generating pharmaceuticals targeting these genes/proteins may prove beneficial in the future.

scholarly journals Anxiolytic effect of GABAergic neurons in the anterior cingulate cortex in a rat model of chronic inflammatory pain

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Fang-bing Shao ◽  
Jun-fan Fang ◽  
Si-si Wang ◽  
Meng-ting Qiu ◽  
Dan-ning Xi ◽  
...  
Keyword(s):  
Chronic Pain ◽  
Anterior Cingulate Cortex ◽  
Rat Model ◽  
Inflammatory Pain ◽  
Pyramidal Neurons ◽  
Cingulate Cortex ◽  
Gabaergic Neurons ◽  
Gabaergic System ◽  
Anterior Cingulate ◽  
Chronic Inflammatory Pain

AbstractChronic pain easily leads to concomitant mood disorders, and the excitability of anterior cingulate cortex (ACC) pyramidal neurons (PNs) is involved in chronic pain-related anxiety. However, the mechanism by which PNs regulate pain-related anxiety is still unknown. The GABAergic system plays an important role in modulating neuronal activity. In this paper, we aimed to study how the GABAergic system participates in regulating the excitability of ACC PNs, consequently affecting chronic inflammatory pain-related anxiety. A rat model of CFA-induced chronic inflammatory pain displayed anxiety-like behaviors, increased the excitability of ACC PNs, and reduced inhibitory presynaptic transmission; however, the number of GAD65/67 was not altered. Interestingly, intra-ACC injection of the GABAAR agonist muscimol relieved anxiety-like behaviors but had no effect on chronic inflammatory pain. Intra-ACC injection of the GABAAR antagonist picrotoxin induced anxiety-like behaviors but had no effect on pain in normal rats. Notably, chemogenetic activation of GABAergic neurons in the ACC alleviated chronic inflammatory pain and pain-induced anxiety-like behaviors, enhanced inhibitory presynaptic transmission, and reduced the excitability of ACC PNs. Chemogenetic inhibition of GABAergic neurons in the ACC led to pain-induced anxiety-like behaviors, reduced inhibitory presynaptic transmission, and enhanced the excitability of ACC PNs but had no effect on pain in normal rats. We demonstrate that the GABAergic system mediates a reduction in inhibitory presynaptic transmission in the ACC, which leads to enhanced excitability of pyramidal neurons in the ACC and is associated with chronic inflammatory pain-related anxiety.

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