Faculty Collaboration Database

Selective block of sensory neuronal T-type/Cav3.2 activity mitigates neuropathic pain behavior in a rat model of osteoarthritis pain. Arthritis Res Ther 2022 Jul 16;24(1):168

Date

07/17/2022

Pubmed ID

35842727

Pubmed Central ID

PMC9287929

DOI

10.1186/s13075-022-02856-0

Scopus ID

2-s2.0-85134262185 (requires institutional sign-in at Scopus site)   2 Citations

Abstract

BACKGROUND: Peripheral and central nociceptive sensitization is a critical pathogenetic component in osteoarthritis (OA) chronic pain. T-type calcium channel 3.2 (Ca_V3.2) regulates neuronal excitability and plays important roles in pain processing. We previously identified that enhanced T-type/Ca_V3.2 activity in the primary sensory neurons (PSNs) of dorsal root ganglia (DRG) is associated with neuropathic pain behavior in a rat model of monosodium iodoacetate (MIA)-induced knee OA. PSN-specific T-type/Ca_V3.2 may therefore represent an important mediator in OA painful neuropathy. Here, we test the hypothesis that the T-type/Ca_V3.2 channels in PSNs can be rationally targeted for pain relief in MIA-OA.

METHODS: MIA model of knee OA was induced in male and female rats by a single injection of 2 mg MIA into intra-knee articular cavity. Two weeks after induction of knee MIA-OA pain, recombinant adeno-associated viruses (AAV)-encoding potent Ca_V3.2 inhibitory peptide aptamer 2 (Ca_V3.2iPA2) that have been characterized in our previous study were delivered into the ipsilateral lumbar 4/5 DRG. Effectiveness of DRG-Ca_V3.2iPA2 treatment on evoked (mechanical and thermal) and spontaneous (conditioned place preference) pain behavior, as well as weight-bearing asymmetry measured by Incapacitance tester, in the arthritic limbs of MIA rats were evaluated. AAV-mediated transgene expression in DRG was determined by immunohistochemistry.

RESULTS: AAV-mediated expression of Ca_V3.2iPA2 selective in the DRG-PSNs produced significant and comparable mitigations of evoked and spontaneous pain behavior, as well as normalization of weight-bearing asymmetry in both male and female MIA-OA rats. Analgesia of DRG-AAV-Ca_V3.2iPA1, another potent Ca_V3.2 inhibitory peptide, was also observed. Whole-cell current-clamp recordings showed that AAV-mediated Ca_V3.2iPA2 expression normalized hyperexcitability of the PSNs dissociated from the DRG of MIA animals, suggesting that Ca_V3.2iPA2 attenuated pain behavior by reversing MIA-induced neuronal hyperexcitability.

CONCLUSIONS: Together, our results add therapeutic support that T-type/Ca_V3.2 in primary sensory pathways contributes to MIA-OA pain pathogenesis and that Ca_V3.2iPAs are promising analgesic leads that, combined with AAV-targeted delivery in anatomically segmental sensory ganglia, have the potential for further development as a peripheral selective T-type/Ca_V3.2-targeting strategy in mitigating chronic MIA-OA pain behavior. Validation of the therapeutic potential of this strategy in other OA models may be valuable in future study.

Author List

Itson-Zoske B, Shin SM, Xu H, Qiu C, Fan F, 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

Animals
Disease Models, Animal
Female
Ganglia, Spinal
Iodoacetic Acid
Male
Neuralgia
Osteoarthritis, Knee
Rats
Rats, Sprague-Dawley
Sensory Receptor Cells