Faculty Collaboration Database

Enhanced T-type calcium channel 3.2 activity in sensory neurons contributes to neuropathic-like pain of monosodium iodoacetate-induced knee osteoarthritis. Mol Pain 2020;16:1744806920963807

Date

10/16/2020

Pubmed ID

33054557

Pubmed Central ID

PMC7570798

DOI

10.1177/1744806920963807

Scopus ID

2-s2.0-85092743914 (requires institutional sign-in at Scopus site)   19 Citations

Abstract

The monosodium iodoacetate knee osteoarthritis model has been widely used for the evaluation of osteoarthritis pain, but the pathogenesis of associated chronic pain is not fully understood. The T-type calcium channel 3.2 (Ca_V3.2) is abundantly expressed in the primary sensory neurons, in which it regulates neuronal excitability at both the somata and peripheral terminals and facilitates spontaneous neurotransmitter release at the spinal terminals. In this study, we investigated the involvement of primary sensory neuron-Ca_V3.2 activation in monosodium iodoacetate osteoarthritis pain. Knee joint osteoarthritis pain was induced by intra-articular injection of monosodium iodoacetate (2 mg) in rats, and sensory behavior was evaluated for 35 days. At that time, knee joint structural histology, primary sensory neuron injury, and inflammatory gliosis in lumbar dorsal root ganglia, and spinal dorsal horn were examined. Primary sensory neuron-T-type calcium channel current by patch-clamp recording and Ca_V3.2 expression by immunohistochemistry and immunoblots were determined. In a subset of animals, pain relief by Ca_V3.2 inhibition after delivery of Ca_V3.2 inhibitor TTA-P2 into sciatic nerve was investigated. Knee injection of monosodium iodoacetate resulted in osteoarthritis histopathology, weight-bearing asymmetry, sensory hypersensitivity of the ipsilateral hindpaw, and inflammatory gliosis in the ipsilateral dorsal root ganglia, sciatic nerve, and spinal dorsal horn. Neuronal injury marker ATF-3 was extensively upregulated in primary sensory neurons, suggesting that neuronal damage was beyond merely knee-innervating primary sensory neurons. T-type current in dissociated primary sensory neurons from lumbar dorsal root ganglia of monosodium iodoacetate rats was significantly increased, and Ca_V3.2 protein levels in the dorsal root ganglia and spinal dorsal horn ipsilateral to monosodium iodoacetate by immunoblots were significantly increased, compared to controls. Perineural application of TTA-P2 into the ipsilateral sciatic nerve alleviated mechanical hypersensitivity and weight-bearing asymmetry in monosodium iodoacetate osteoarthritis rats. Overall, our findings demonstrate an elevated Ca_V3.2 expression and enhanced function of primary sensory neuron-T channels in the monosodium iodoacetate osteoarthritis pain. Further study is needed to delineate the importance of dysfunctional primary sensory neuron-Ca_V3.2 in osteoarthritis pain.

Author List

Shin SM, Cai Y, Itson-Zoske B, Qiu C, Hao X, Xiang H, Hogan QH, Yu H

Authors

Quinn H. Hogan MD Professor in the Anesthesiology department at Medical College of Wisconsin
Hongwei Yu MD Professor in the Anesthesiology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Activating Transcription Factor 3
Animals
Behavior Rating Scale
Benzamides
Calcium Channel Blockers
Calcium Channels, T-Type
Diphosphates
Disease Models, Animal
Ganglia, Spinal
Imidazoles
Immunohistochemistry
Inflammation
Male
Neuralgia
Nociceptors
Osteoarthritis, Knee
Piperidines
Rats
Rats, Sprague-Dawley
Sciatic Nerve
Sensory Receptor Cells
Up-Regulation