UNLABELLED: Controlling pain in burn-injured patients poses a major clinical challenge. Recent findings suggest that reducing the activity of the voltage-gated sodium channel Nav1.7 in primary sensory neurons could provide improved pain control in burn-injured patients. Here, we report that partial thickness scalding-type burn injury on the rat paw upregulates Nav1.7 expression in primary sensory neurons 3 h following injury. The injury also induces upregulation in phosphorylated cyclic adenosine monophosphate response element-binding protein (p-CREB), a marker for nociceptive activation in primary sensory neurons. The upregulation in p-CREB occurs mainly in Nav1.7-immunopositive neurons and exhibits a peak at 5 min and, following a decline at 30 min, a gradual increase from 1 h post-injury. The Nav1.7 blocker protoxin II (ProTxII) or morphine injected intraperitoneally 15 min before or after the injury significantly reduces burn injury-induced spinal upregulation in phosphorylated serine 10 in histone H3 and phosphorylated extracellular signal-regulated kinase 1/2, which are both markers for spinal nociceptive processing. Further, ProTxII significantly reduces the frequency of spontaneous excitatory post-synaptic currents in spinal dorsal horn neurons following burn injury. Together, these findings indicate that using Nav1.7 blockers should be considered to control pain in burn injury. KEY MESSAGES: • Burn injury upregulates Nav1.7 expression in primary sensory neurons. • Burn injury results in increased activity of Nav1.7-expressing primary sensory neurons. • Inhibiting Nav1.7 by protoxin II reduces spinal nociceptive processing. • Nav1.7 represents a potential target to reduce pain in burn injury.

Department of Anaesthetics Chelsea and Westminster Hospital NHS Trust 369 Fulham Road London SW10 9NH UK

Department of Functional Morphology Institute of Physiology The Czech Academy of Sciences Prague Czech Republic

Department of Physiology Faculty of Science Charles University Prague Czech Republic

MTA DE NAP B Pain Control Research Group Department of Anatomy Histology and Embryology University of Debrecen Debrecen 4012 Hungary

Nociception Group Section of Anaesthetics Pain Medicine and Intensive Care Department of Surgery and Cancer Imperial College London Chelsea and Westminster Hospital 369 Fulham Road London SW10 9NH UK

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