Human α1-Antitrypsin Inhibits Nociceptor Excitability and Relieves Inflammatory and Neuropathic Pain

Chronic pain affects hundreds of millions of people and remains poorly managed, as the most effective drugs, including opioids, carry side effects that limit long-term use. Because inflammation drives both the initiation and maintenance of chronic pain, anti-inflammatory mechanisms are an attractive analgesic target. We investigated human alpha-1 antitrypsin (hAAT), a serine proteinase inhibitor with potent anti-inflammatory activity and established protection across disease models, as a candidate analgesic, using Aralast NP^®, a clinical-grade, already-approved formulation that makes findings directly translatable. Using calcium imaging and patch-clamp electrophysiology in mouse dorsal root ganglion (DRG) neurons, we found that hAAT reduced activation of low-voltage-activated Ca²⁺ channels and dampened intrinsic excitability. Veratridine-evoked Ca²⁺ responses, a sodium-channel-dependent readout of nociceptor activity, were suppressed by hAAT to a degree comparable to the selective sodium channel inhibitors ProTx-II (Na_V1.7) and VX-548 (Na_V1.8), driven by loss of the nociceptor-associated response profiles. In vivo, hAAT decreased pain sensitivity and pain-associated behaviors in both inflammatory and neuropathic models. Together, these findings reveal a mechanism by which hAAT suppresses nociceptor activity and position Aralast NP^® as a safe, effective candidate for treating chronic pain.