Selective block of sensory neuronal T-type/Cav3.2 activity mitigates neuropathic pain behavior in a rat model of osteoarthritis pain

Abstract

Abstract Background Peripheral and central nociceptive sensitization is a critical pathogenetic component in osteoarthritis (OA) chronic pain. T-type calcium channel 3.2 (CaV3.2) regulates neuronal excitability and plays important roles in pain processing. We previously identified that enhanced T-type/CaV3.2 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/CaV3.2 may therefore represent an important mediator in OA painful neuropathy. Here, we test the hypothesis that the T-type/CaV3.2 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 CaV3.2 inhibitory peptide aptamer 2 (CaV3.2iPA2) that have been characterized in our previous study were delivered into the ipsilateral lumbar 4/5 DRG. Effectiveness of DRG-CaV3.2iPA2 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 CaV3.2iPA2 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-CaV3.2iPA1, another potent CaV3.2 inhibitory peptide, was also observed. Whole-cell current-clamp recordings showed that AAV-mediated CaV3.2iPA2 expression normalized hyperexcitability of the PSNs dissociated from the DRG of MIA animals, suggesting that CaV3.2iPA2 attenuated pain behavior by reversing MIA-induced neuronal hyperexcitability. Conclusions Together, our results add therapeutic support that T-type/CaV3.2 in primary sensory pathways contributes to MIA-OA pain pathogenesis and that CaV3.2iPAs 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/CaV3.2-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.