Abstract
Tetrodotoxin-resistant (TTX-R) sodium channels NaV1.8 and NaV1.9 in sensory neurons were known as key pain modulators. Comparing with the widely reported NaV1.8, roles of NaV1.9 on inflammatory pain are poorly studied by antisense-induced specific gene knockdown. Here, we used molecular, electrophysiological and behavioral methods to examine the effects of antisense oligodeoxynucleotide (AS ODN) targeting NaV1.8 and NaV1.9 on inflammatory pain. Following complete Freund's adjuvant (CFA) inflammation treatment, NaV1.8 and NaV1.9 in rat dorsal root ganglion (DRG) up-regulated mRNA and protein expressions and increased sodium current densities. Immunohistochemical data demonstrated that NaV1.8 mainly localized in medium and small-sized DRG neurons, whereas NaV1.9 only expressed in small-sized DRG neurons. Intrathecal (i.t.) delivery of AS ODN was used to down-regulate NaV1.8 or NaV1.9 expressions confirmed by immunohistochemistry and western blot. Unexpectedly, behavioral tests showed that only NaV1.8 AS ODN, but not NaV1.9 AS ODN could reverse CFA-induced heat and mechanical hypersensitivity. Our data indicated that TTX-R sodium channels NaV1.8 and NaV1.9 in primary sensory neurons played distinct roles in CFA-induced inflammatory pain and suggested that antisense oligodeoxynucleotide-mediated blocking of key pain modulator might point toward a potential treatment strategy against certain types of inflammatory pain.
Highlights
Chronic inflammatory pain is worldwide medical problem and with only partial or low efficacy treatment options currently available [1]
Following the establishment of complete Freund’s adjuvant (CFA)-induced inflammatory heat and mechanical pain hypersensitivity (Figure S1), we examined mRNA expressions of fiveisoforms of VGSCs (NaV1.1, NaV1.6, NaV1.7, NaV1.8, NaV1.9) that mainly expressed in dorsal root ganglion (DRG) neurons, but not in spinal cord (Figure S2) [15,22]
We found that NaV1.8 mainly expressed in medium and small-sized DRG neurons that rarely contain NF-200, whereas NaV1.9 just appeared in small-sized DRG neurons that completely not colocalized with NF-200 in naive rats (Figure 1C)
Summary
Chronic inflammatory pain is worldwide medical problem and with only partial or low efficacy treatment options currently available [1]. Investigations have shown that voltage-gated sodium channels, especially tetrodotoxin-resistant (TTX-R) NaV1.8 and NaV1.9, provided the potential therapeutic targets for inflammatory pain [2,3,4,5]. Several problems have to overcome for the successful application of TTX-R sodium channel blocking drugs. NaV1.8 or NaV1.9 selective blockers with analgesic activity was hard to explore due to the high degree of amino acid sequence homology among the multiple subtypes of VGSCs [6]. Various old (carbamazepine, phenytoin, lamotrigine and zonisamide) and newly developed (oxcarbazepine, crobenetine) sodium channel blockers affect other pathological processes such as epilepsy, spasticity, stoke or psychiatry [8,9]. Analgesic strategies beyond direct blocking NaV1.8 or NaV1.9 at protein levels should be considered for inflammatory pain modulation
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