1. Mechanosensitive ion channels in articular nociceptors drive mechanical allodynia in osteoarthritis
- Author
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B.H. He, Albena Davidova, Reza Sharif-Naeini, Marine Christin, and Stephanie Mouchbahani-Constance
- Subjects
Male ,Nociception ,0301 basic medicine ,Patch-Clamp Techniques ,Biomedical Engineering ,TRPV1 ,Mechanotransduction, Cellular ,Ion Channels ,Injections, Intra-Articular ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Mechanosensitive ion channel ,Rheumatology ,medicine ,Animals ,Orthopedics and Sports Medicine ,Patch clamp ,Enzyme Inhibitors ,business.industry ,Nociceptors ,Osteoarthritis, Knee ,Iodoacetic Acid ,Posterior Horn Cells ,030104 developmental biology ,Allodynia ,Hyperalgesia ,Anesthesia ,Nociceptor ,Mechanosensitive channels ,medicine.symptom ,business ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Summary Objective Osteoarthritis (OA) is a disabling and highly prevalent condition affecting millions worldwide. Pain is the major complaint of OA patients and is presently inadequately managed. It manifests as mechanical allodynia, a painful response to innocuous stimuli such as joint movement. Allodynia is due in part to the sensitization of articular nociceptors to mechanical stimuli. These nociceptors respond to noxious mechanical stimuli applied to their terminals via the expression of depolarizing high-threshold mechanosensitive ion channels (MSICs) that convert painful mechanical forces into electrical signals. In this study, we examined the contribution of MSICs to mechanical allodynia in a mouse model of OA. Method Sodium mono-iodoacetate (MIA) was injected in the left knee of adult male Trpv1:Cre; GFP mice. Primary mechanical allodynia was monitored using the knee-bend test. Single-channel patch clamp electrophysiology was performed on visually-identified knee-innervating nociceptors. Dorsal horn neuronal activation was assessed by Fos immunoreactivity. Results In examining the gating properties of MSICs of naive and OA mice, we discovered that their activation threshold is greatly reduced, causing their opening at significantly lower stimuli intensities. Consequently, nociceptors are activated by mild mechanical stimuli. These channels are reversibly inhibited by the selective MSIC inhibitor GsMTx4, and the intra-articular injection of this peptide significantly reduced the activation of dorsal horn nociceptive circuits and primary mechanical allodynia in OA mice. Conclusions These results suggest that MSICs are sensitized during OA and directly contribute to mechanical allodynia. They therefore represent potential therapeutic targets in the treatment of OA pain.
- Published
- 2017
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