Microglial Panx1 is a Spinal Determinant of Arthritis Joint Pain

Mousseau, Michael James

Microglial Panx1 is a Spinal Determinant of Arthritis Joint Pain

dc.contributor.advisor	Trang, Tuan
dc.contributor.advisor	Matyas, John Robert
dc.contributor.author	Mousseau, Michael James
dc.contributor.committeemember	Altier, Christophe
dc.contributor.committeemember	Salo, Paul T.
dc.date	2018-11
dc.date.accessioned	2018-10-09T18:35:09Z
dc.date.available	2018-10-09T18:35:09Z
dc.date.issued	2018-09-27
dc.description.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.	en_US
dc.identifier.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	en_US
dc.identifier.doi	http://dx.doi.org/10.11575/PRISM/33142
dc.identifier.uri	http://hdl.handle.net/1880/108791
dc.language.iso	eng
dc.publisher.faculty	Cumming School of Medicine
dc.publisher.faculty	Graduate Studies
dc.publisher.institution	University of Calgary	en
dc.publisher.place	Calgary	en
dc.rights	University of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission.
dc.subject	pain
dc.subject	Microglia
dc.subject	Pannexin-1
dc.subject.classification	Neuroscience	en_US
dc.title	Microglial Panx1 is a Spinal Determinant of Arthritis Joint Pain
dc.type	doctoral thesis
thesis.degree.discipline	Neuroscience
thesis.degree.grantor	University of Calgary
thesis.degree.name	Doctor of Philosophy (PhD)
ucalgary.item.requestcopy	true