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Published on: January 27, 2014
Markedly attenuated acute and chronic pain responses in mice lacking adenylyl cyclase-5
1Division of Nano Science and Department of Biology, College of Natural Science, Ewha Womans University, Seoul, 120-750, Republic of Korea.
Abstract:
Chronic inflammatory and neuropathic pain is often difficult to manage using conventional remedies. The underlying mechanisms and therapeutic strategies required for the management of chronic pain need to be urgently established. The cyclic AMP (cAMP) second messenger system has been implicated in the mechanism of nociception, and the inhibition of the cAMP pathway by blocking the activities of adenylyl cyclase (AC) and protein kinase A has been found to prevent chronic pain in animal models. However, little is known regarding which of the 10 known isoforms of AC are involved in nociceptive pathways. Therefore, we investigated the potential pronociceptive function of AC5 in nociception using recently developed AC5 knockout mice (AC5-/-). We found that AC5-/- mice show markedly attenuated pain-like responses in acute thermal and mechanical pain tests as compared with the wildtype control. Also, AC5-/- mice display hypoalgesic responses to inflammatory pain induced by subcutaneous formalin injection into hindpaws, and to non-inflammatory and inflammatory visceral pain induced by injecting magnesium sulfate or acetic acid into the abdomen. Moreover, AC5-/- mice show strongly suppressed mechanical and thermal allodynia in two nerve injury-induced neuropathic pain models. These results suggest that AC5 is essential for acute and chronic pain, and that AC5 knockout mice provide a useful model for the evaluation of the pathophysiological mechanisms of pain.
Insights
Adenylyl cyclase 5 (AC5) plays a crucial role in pain signaling. AC5 knockout mice demonstrate reduced responses to various pain types, highlighting AC5 as a potential therapeutic target for pain management.
Area of Science:
- Neuroscience
- Pain Research
- Molecular Biology
Background:
- Chronic pain, including inflammatory and neuropathic pain, presents significant management challenges.
- The cyclic AMP (cAMP) signaling pathway is implicated in nociception, with adenylyl cyclase (AC) inhibition showing promise in preclinical pain models.
- Specific AC isoforms involved in pain pathways remain largely unidentified.
Purpose of the Study:
- To investigate the role of adenylyl cyclase 5 (AC5) in nociception and pain processing.
- To evaluate the pronociceptive function of AC5 using AC5 knockout mice (AC5-/-).
Main Methods:
- Utilized AC5 knockout mice (AC5-/-) and wildtype littermate controls.
- Assessed pain-like behaviors in response to acute thermal and mechanical stimuli.
- Evaluated responses to inflammatory pain models (formalin injection) and visceral pain models (magnesium sulfate, acetic acid).
- Investigated neuropathic pain models involving nerve injury to assess allodynia.
Main Results:
- AC5-/- mice exhibited significantly reduced pain responses in acute thermal and mechanical tests compared to wildtype controls.
- AC5 knockout attenuated inflammatory and visceral pain responses.
- Mechanical and thermal allodynia in neuropathic pain models were strongly suppressed in AC5-/- mice.
Conclusions:
- AC5 is essential for the development and maintenance of both acute and chronic pain states.
- AC5 knockout mice represent a valuable preclinical model for studying pain pathophysiology.
- Targeting AC5 may offer a novel therapeutic strategy for managing diverse pain conditions.
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