Background & Aims
Developing effective non-addictive analgesics is critical to addressing the chronic pain and the opioid epidemic. Pain-associated genes identified from human diseases associated with neuropathic pain could become therapeutic targets with lower risk of dependence. Fibrodysplasia ossificans progressiva (FOP) is a hereditary disease of heterotopic ossification (HO) carrying an arginine206 to histidine gain-of-function point mutation (R206H) in the type I BMP receptor Activin A Receptor Type 1 (ACVR1), also known as Activin receptor-like kinase 2 (ALK2)1. We recently reported that adult FOP patients have ongoing heat and mechanical hypersensitivity2. Utilizing FOP patient iPSC-derived nociceptive sensory neurons (SNs), we demonstrated that the R206H mutation is both necessary and sufficient for the hyperexcitability of nociceptors, a hallmark of neuropathic pain. Here we investigated whether neuronal ACVR1/ALK2 hyperactivity is also relevant to more common neuropathic pain conditions.
Methods
We generated transgenic mice that selectively express the activating R206H in SNs and baseline pain behaviors were examined. Potential R206H downstream targets identified by transcriptomic profiling of DRG cells were further confirmed RT-PCR and in situ hybridization.
Results
Activating R206H in SNs led to a recapitulation of the mechanical and heat hypersensitivity observed in FOP patients. Among R206H-modulated genes, Cacna2d2 which encodes the voltage-gated calcium channel subunit a2d2, co-binding site of gabapentinoids3,4, was dramatically downregulated. Interestingly, reducing Cacna2d2 expression in naïve mice leads to mechanical hypersensitivity which can be reversed by an ALK2 inhibitor5, revealing a close association between ALK2 and a2d2. Moreover, as normal Alk2 expression is profoundly increased in axotomized DRG neurons following spared nerve injury (SNI)2, we further demonstrated that inhibiting injury-induced neuronal ALK2 signaling in the DRG by an ALK2 inhibitor, prevented nerve injury-induced mechanical hypersensitivity and reversed persistent pain. As the translatability of evoked pain behavioral assay has been increasingly debated, we confirmed the analgesic potential of the ALK2 inhibitor in a freely moving animal with unilateral SNI6.
Conclusions
We provide evidence to support the targetability of peripheral neuronal ACVR1/ALK2 for the treatment of neuropathic pain not only in FOP patients, but also in patients with more common neuropathic pain conditions.
References
1.Shore EM, Xu M, Feldman GJ, et al. A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva. Nat Genet. May 2006;38(5):525-7. doi:10.1038/ng1783
2.Yu X, Ton AN, Niu Z, et al. An ACVR1 activating mutation causes neuropathic pain and sensory neuron hyperexcitability in humans. Pain. Apr 20 2022;doi:10.1097/j.pain.0000000000002656
3.Gee NS, Brown JP, Dissanayake VU, Offord J, Thurlow R, Woodruff GN. The novel anticonvulsant drug, gabapentin (Neurontin), binds to the alpha2delta subunit of a calcium channel. J Biol Chem. Mar 8 1996;271(10):5768-76. doi:10.1074/jbc.271.10.5768
4.Gong HC, Hang J, Kohler W, Li L, Su TZ. Tissue-specific expression and gabapentin-binding properties of calcium channel alpha2delta subunit subtypes. J Membr Biol. Nov 1 2001;184(1):35-43. doi:10.1007/s00232-001-0072-7
5.Yu PB, Deng DY, Lai CS, et al. BMP type I receptor inhibition reduces heterotopic ossification. Nat Med. Dec 2008;14(12):1363-9. doi:10.1038/nm.1888
6.Zhang Z, Roberson DP, Kotoda M, et al. Automated preclinical detection of mechanical pain hypersensitivity and analgesia. Pain. Dec 1 2022;163(12):2326-2336. doi:10.1097/j.pain.0000000000002680
Presenting Author
Xiaobing Yu
Poster Authors
Xiaobing Yu
MD
University of California, San Francisco
Lead Author
Topics
- Treatment/Management: Pharmacology: Novel Targets