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 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.

Intrathecal Knockdown of Adenylyl Cyclase 1 Attenuates Morphine Tolerance and Withdrawal in Mice

2021 ◽  
Vol 22 (5) ◽  
pp. 578-579
Author(s):  
Alexis Doucette ◽  
Kayla Johnson ◽  
Val Watts ◽  
Amanda Klein
Keyword(s):  
Adenylyl Cyclase ◽  
Morphine Tolerance ◽  
Adenylyl Cyclase 1

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.

Opioid-induced hyperalgesia: Pathophysiology and clinical implications

2018 ◽  
Vol 4 (3) ◽  
pp. 123 ◽  
Author(s):  
Sukanya Mitra, MD, MAMS
Keyword(s):  
Treatment Strategies ◽  
Opioid Tolerance ◽  
Diverse Range ◽  
Opioid Rotation ◽  
Opioid Dose ◽  
Manual Search ◽  
Opioid Administration ◽  
Opioid Induced Hyperalgesia ◽  
Pain Symptoms ◽  
Underlying Pathophysiology

Background: Opioid-induced hyperalgesia (OIH) refers to a phenomenon whereby opioid administration results in a lowering of pain threshold, clinically manifest as apparent opioid tolerance, worsening pain despite accelerating opioid doses, and abnormal pain symptoms such as allodynia.Aim: The current review, while providing a clinically oriented updated overview on the pathophysiology of OIH, focuses predominantly on evidence-based clinical and management aspects of this important and often baffling phenomenon.Method: Online and manual search using key words such as opioid-induced hyperalgesia, opioid-induced abnormal pain sensitivity, opioid hyperalgesia, opioidinduced paradoxical pain, or opioid-induced abnormal pain, followed by full-text access and further crossreferencing.Results: The underlying pathophysiology of this phenomenon, although still unclear, appears to be related to an opioid-induced imbalance between the internal antinociceptive and pronociceptive systems. Clinical differentiation of an apparent opioid tolerance state includes OIH. Once diagnosed or provisionally considered, treatment strategies could include opioid dose reduction, opioid rotation, use of agents with NMDA receptor antagonism, and a properly timed coxib.Conclusion: Despite initial skepticism and reservations, the phenomenon of OIH in humans is now accepted a clinical reality and a challenge faced by anesthesiologists, intensivists, pain specialists, and other workers in a diverse range of settings from perioperative care to palliative care medicine.

Focused Library Screening for Isoform Selective Adenylyl Cyclase 1 Inhibitors as Non‐Opioid Alternatives for Chronic and Inflammatory Pain

2020 ◽  
Vol 34 (S1) ◽  
pp. 1-1
Author(s):  
Michael P. Hayes ◽  
Todd R. Wiernicki ◽  
Maria Angeles Martinez-Grau ◽  
Kevin D. Burris ◽  
Val J. Watts
Keyword(s):  
Adenylyl Cyclase ◽  
Inflammatory Pain ◽  
Library Screening ◽  
Adenylyl Cyclase 1

scholarly journals Opioid Induced Hyperalgesia, a Research Phenomenon or a Clinical Reality? Results of a Canadian Survey

2020 ◽  
Vol 10 (2) ◽  
pp. 27
Author(s):  
Grisell Vargas-Schaffer ◽  
Suzie Paquet ◽  
Andrée Neron ◽  
Jennifer Cogan
Keyword(s):  
Chronic Pain ◽  
Nmda Antagonist ◽  
Treatment Modalities ◽  
Clinical Test ◽  
Physician Practice ◽  
Clinical Tests ◽  
Opioid Rotation ◽  
Number Of Patients ◽  
Opioid Induced Hyperalgesia ◽  
Age Range

Background: Very little is known regarding the prevalence of opioid induced hyperalgesia (OIH) in day to day medical practice. The aim of this study was to evaluate the physician’s perception of the prevalence of OIH within their practice, and to assess the level of physician’s knowledge with respect to the identification and treatment of this problem. Methods: An electronic questionnaire was distributed to physicians who work in anesthesiology, chronic pain, and/or palliative care in Canada. Results: Of the 462 responses received, most were from male (69%) anesthesiologists (89.6%), in the age range of 36 to 64 years old (79.8%). In this study, the suspected prevalence of OIH using the average number of patients treated per year with opioids was 0.002% per patient per physician practice year for acute pain, and 0.01% per patient per physician practice year for chronic pain. Most physicians (70.2%) did not use clinical tests to help make a diagnosis of OIH. The treatment modalities most frequently used were the addition of an NMDA antagonist, combined with lowering the opioid doses and using opioid rotation. Conclusions: The perceived prevalence of OIH in clinical practice is a relatively rare phenomenon. Furthermore, more than half of physicians did not use a clinical test to confirm the diagnosis of OIH. The two main treatment modalities used were NMDA antagonists and opioid rotation. The criteria for the diagnosis of OIH still need to be accurately defined.

scholarly journals Analgesic Efficacy of a Combination of Fentanyl and a Japanese Herbal Medicine “Yokukansan” in Rats with Acute Inflammatory Pain

Medicines ◽  
2020 ◽  
Vol 7 (12) ◽  
pp. 75
Author(s):  
Yuko Akanuma ◽  
Mami Kato ◽  
Yasunori Takayama ◽  
Hideshi Ikemoto ◽  
Naoki Adachi ◽  
...  
Keyword(s):  
Inflammatory Pain ◽  
Late Phase ◽  
Analgesic Efficacy ◽  
Opioid Tolerance ◽  
High Dose ◽  
Erk Pathway ◽  
Single High Dose ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Combined Use

Background: Fentanyl can induce acute opioid tolerance and postoperative hyperalgesia when administered at a single high dose; thus, this study examined the analgesic efficacy of a combination of fentanyl and Yokukansan (YKS). Methods: Rats were divided into control, formalin-injected (FOR), YKS-treated+FOR (YKS), fentanyl-treated+FOR (FEN), and YKS+FEN+FOR (YKS+FEN) groups. Acute pain was induced via subcutaneous injection of formalin into the paw. The time engaged in pain-related behavior was measured. Results: In the early (0–10 min) and intermediate (10–20 min) phases, pain-related behavior in the YKS+FEN group was significantly inhibited compared with the FOR group. In the late phase (20–60 min), pain-related behavior in the FEN group was the longest and significantly increased compared with the YKS group. We explored the influence on the extracellular signal-regulated kinase (ERK) pathway in the spinal cord, and YKS suppressed the phosphorylated ERK expression, which may be related to the analgesic effect of YKS in the late phase. Conclusions: These findings suggest that YKS could reduce the use of fentanyl and combined use of YKS and fentanyl is considered clinically useful.

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

2020 ◽  
Vol 17 (3) ◽  
pp. 861-873 ◽  
Author(s):  
Xu-Hui Li ◽  
Qi-Yu Chen ◽  
Min Zhuo
Keyword(s):  
Chronic Pain ◽  
Adenylyl Cyclase
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