Hyperpolarization-activated cyclic nucleotide–gated channels contribute to spontaneous activity in L4 C-fiber nociceptors, but not Aβ-non-nociceptors, after axotomy of L5-spinal nerve in the rat in vivo

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Abstract

Peripheral neuropathic pain associated with partial nerve injury is believed to be driven partly by aberrant spontaneous activity (SA) in both injured and uninjured dorsal root ganglion (DRG) neurons. The underlying ionic mechanisms are not fully understood, but hyperpolarization-activated cyclic nucleotide–gated (HCN) channels which underlie the excitatory Ih current have been implicated in SA generation in axotomized A-fiber neurons after L5-spinal nerve ligation/axotomy (SNL/SNA). Here, using a modified model of SNA (mSNA) which involves, in addition to L5-SNA, loose ligation of the L4-spinal nerve with neuroinflammation-inducing chromic gut, we examined whether HCN channels also contribute to SA in the adjacent L4-neurons. Intracellular recordings from L4-DRG neurons in control rats, and L4-DRG neurons in mSNA rats were made using in vivo voltage- and current-clamp techniques. Compared with control, L4 C-nociceptors and Aβ-low-threshold mechanoreceptors (LTMs) exhibited SA 7 days after mSNA. This was accompanied, in C-nociceptors, by a significant increase in Ih amplitude, the percentage of Ih-expressing neurons, and Ih activation rate. Hyperpolarization-activated cyclic nucleotide–gated channel blockade with ZD7288 (10 mg/kg, intravenously) suppressed SA in C-nociceptors, but not Aβ-LTMs, and caused in C-nociceptors, membrane hyperpolarization and a decrease in Ih activation rate. Furthermore, intraplantar injection of ZD7288 (100 μM) was found to be as effective as gabapentin (positive control) in attenuating cold hypersensitivity in mSNA rats. These findings suggest that HCN channels contribute to nerve injury–induced SA in L4 C-nociceptors, but not Aβ-LTMs, and that ZD7288 exerts its analgesic effects by altering Ih activation properties and/or causing membrane hyperpolarization in L4 C-nociceptors.

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