Abstract
Expression of the voltage-gated sodium channel NaV1.7 in sensory neurons is required for pain sensation. We examined the role of NaV1.7 in the dorsal horn of the spinal cord using an epitope-tagged NaV1.7 knock-in mouse. Immuno-electron microscopy showed the presence of NaV1.7 in dendrites of superficial dorsal horn neurons, despite the absence of mRNA. Rhizotomy of L5 afferent nerves lowered the levels of NaV1.7 in the dorsal horn. Peripheral nervous system-specific NaV1.7 null mutant mice showed central deficits, with lamina II dorsal horn tonic firing neurons more than halved and single spiking neurons more than doubled. NaV1.7 blocker PF05089771 diminished excitability in dorsal horn neurons but had no effect on NaV1.7 null mutant mice. These data demonstrate an unsuspected functional role of primary afferent neuron-generated NaV1.7 in dorsal horn neurons and an expression pattern that would not be predicted by transcriptomic analysis.
Highlights
The problem of pain continues to grow, and new analgesic approaches are urgently required [1]
Immunohistochemical studies showed that the Tandem Affinity Purification (TAP)–tagged NaV1.7 is expressed in laminae I and II and part of lamina III in the spinal cord on the basis of coexpression with substance P, prostatic acid phosphatase (PAP), and vesicular glutamate transporter 1 (Fig. 1A)
Immuno-EM showed that the TAP-tagged NaV1.7 is present in presynaptic sites of central terminals of peripheral sensory neurons and in postsynaptic sites in dendrites in spinal cord neurons, as defined by ultrastructural criteria (Fig. 1B) [15, 16]
Summary
The problem of pain continues to grow, and new analgesic approaches are urgently required [1]. The sodium channel NaV1.7 expressed in sensory neurons is required for pain perception in mice and humans [5]. NaV1.7 has been assumed to play an essential role in generating nociceptive spiking in sensory neurons. It has other roles in pain pathways. Deletion of NaV1.7 in sensory neurons leads to enhanced expression of opioid peptides and potentiated opioid receptor activity [7, 8]. Much of the analgesia associated with loss of function of NaV1.7 in mice and humans can be reversed with the opioid antagonist naloxone, while NaV1.7 antagonist action is greatly potentiated by low-dose opioids or enkephalinase blockers [9, 10]. NaV1.7 has an unusual role as an integrator of synaptic input in the hypothalamus [11]
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