Details

Autor(en) / Beteiligte

• He, Haitian (Billy)

Titel

The Role of MechanoSensitive Ion Channels in Osteoarthritis Pain

Ort / Verlag

ProQuest Dissertations & Theses

Erscheinungsjahr

2015

Quelle

ProQuest Dissertations & Theses A&I

Beschreibungen/Notizen

• Osteoarthritis (OA) is a disabling and prevalent condition affecting 27 million US citizens and 4.2 million Canadians. Pain is the primary symptom of OA and it is manifested as mechanical hypersensitivity to joint palpation/movement, although the underlying mechanisms are poorly understood. This project aims to examine changes that occur in mechanosensitive ion channels (MSCs) of joint innervating pain-sensing neurons (nociceptors) during OA. These channels transduce mechanical stimuli into electrical signals. Using a mouse model that produces OA-like joint pathophysiology and pain, we assess if alteration in the gating properties of MSCs in joint-innervating nociceptors is a contributor to OA pain. We hypothesize that MSCs are sensitized to mechanical stimulation in OA and blocking their activity will reduce pain behaviours in OA mice. Using acutely dissociated neurons from healthy and OA mice, we performed electrophysiology on knee-innervating nociceptors to examine the properties of MSCs. Our data shows that MSCs from OA nociceptors have a reduced mechanical activation threshold, which results in an increased mechanically-evoked current. Analysis of the frequency of patches containing MSCs demonstrates that nociceptors of OA mice do not have an increased density of active MSCs at the membrane. Furthermore, single channel iV curves demonstrate that it is likely that the same MSC is present in both naïve and disease states. Lastly, GsTMx4, a blocker of MSCs, blocks MSCs present in knee-innervating nociceptors. Finally, in behavioral experiments, intra-articular injection of GsMTx4 in the OA knee produces significant analgesia. In summary, our model for OA pain shows that in nociceptors, MSCs are sensitized to mechanical stimuli and contribute to OA pain. Furthermore, targeting these channels in OA knees may be a valuable therapeutic strategy for managing OA pain.