Microglial Panx1 is a Spinal Determinant of Arthritis Joint Pain
Date
2018-09-27
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Abstract
Pain is a debilitating feature of arthritis. Despite recent advances in treating joint inflammation and the widespread use of pain medications by arthritis patients, adequate pain control is an ongoing medical problem. A major challenge is that joint pain is poorly understood: some individuals with severe joint damage report little pain, whereas paradoxically others with seemingly minor joint damage complain of debilitating pain. This thesis examines how microglia in the spinal cord signal through pannexin-1 (Panx1) channels to mediate joint pain. My overarching hypothesis is that microglial Panx1 channels critically modulate arthritis joint pain and that silencing peripheral afferents suppresses microglial reactivity following joint injury. In rats, joint pain caused by intra-articular injection of monosodium iodoacetate (MIA) was associated with spinal adenosine triphosphate (ATP) release and an increase in spinal microglial reactivity. Here, I provide evidence that both C- and A-afferents modulate the development of mechanical allodynia in a model of MIA-induced joint pain. I also demonstrate that specific ablation of either peptidergic or non-peptidergic afferents can attenuate mechanical allodynia, decrease spinal microglial reactivity and suppress extracellular ATP concentration in the CSF of animals with MIA-induced joint damage. Following joint injury, I show a microglial-specific upregulation of P2X7-receptors (P2X7R). P2X7Rs drive pannexin-1 (Panx1) channel activation and, in rats with mechanical allodynia, Panx1 function is increased in spinal microglia. Specifically, I demonstrate that microglial Panx1-mediated release of the pro-inflammatory cytokine interleukin-1 (IL-1) induces mechanical allodynia in the MIA-injected hindlimb. Furthermore, I provide evidence that mice with a microglial-specific genetic deletion of Panx1 are protected from developing mechanical allodynia. Finally, I show that the clinically utilized broad-spectrum Panx1 blocker, probenecid, attenuates MIA-induced mechanical allodynia in two experimental models of arthritis and normalizes responses in the dynamic weight-bearing test, without impacting acute nociception. In conclusion, this thesis identifies that spinal microglial Panx1 channels are critically involved in the development of arthralgia and that Panx1-targeted therapy is a new mechanistic approach for alleviating joint pain.
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Keywords
pain, Microglia, Pannexin-1
Citation
Mousseau, M. J. (2018). Microglial Panx1 is a Spinal Determinant of Arthritis Joint Pain (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca. doi:10.11575/PRISM/33142