A SCN10A SNP biases human pain sensitivity

Abstract

Background: Nav1.8 sodium channels, encoded by SCN10A, are preferentially expressed in nociceptive neurons and play an important role in human pain. Although rare gain-of-function variants in SCN10A have been identified in individuals with painful peripheral neuropathies, whether more common variants in SCN10A can have an effect at the channel level and at the dorsal root ganglion, neuronal level leading to a pain disorder or an altered normal pain threshold has not been determined. Results: Candidate single nucleotide polymorphism association approach together with experimental pain testing in human subjects was used to explore possible common SCN10A missense variants that might affect human pain sensitivity. We demonstrated an association between rs6795970 (G > A; p.Ala1073Val) and higher thresholds for mechanical pain in a discovery cohort (496 subjects) and confirmed it in a larger replication cohort (1005 female subjects). Functional assessments showed that although the minor allele shifts channel activation by À4.3 mV, a proexcitatory attribute, it accelerates inactivation, an antiexcitatory attribute, with the net effect being reduced repetitive firing of dorsal root ganglion neurons, consistent with lower mechanical pain sensitivity. Conclusions: At the association and mechanistic levels, the SCN10A single nucleotide polymorphism rs6795970 biases human pain sensitivity.

Sodium channels in pain disorders: pathophysiology and prospects for treatment

“…De novo gain-of-function mutations of Na v 1.8 that produce DRG neuron hyperexcitability have been found in 4% of a group of 393 consecutive patients diagnosed with small fiber neuropathy (SFN) at one medical center, including familial episodic pain syndrome (FEPS2, OMIM#61551), establishing a role for this channel in pathogenesis [19; 59], and a single nucleotide polymorphism biases experimental pain in healthy human subjects [46]. The gain-of-function attributes that these mutations confer on Na v 1.8 include hyperpolarized voltage-dependence of activation, accelerated recovery from inactivation, enhanced ramp current and impaired inactivation.…”

Single nucleotide polymorphisms associated with postoperative inadequate analgesia after single-port VATS in Chinese population

“…They also demonstrated an association between SCN10A rs6795970 and higher thresholds for mechanical pain in experimental pain testing. [15] However, in our study, we identified that patients with the 3312Tallele (3312G>T) and A allele (rs6795970) had a higher risk of presenting with inadequate analgesia.…”

“…They are preferentially expressed in dorsal root ganglion sensory neurons and sympathetic ganglia and significantly influence nociceptor excitability. [15,38,39] Recent genetic studies have identified rare and common mutations in SCN9A and SCN10A as contributory both in chronic pain conditions and postoperative pain. [15,16,39] Guangyou Duan et al reported that 3312G>T (SCN9A), a nonsynonymous SNP leading to the amino acid substitution V1104L in human Nav1.7, was associated with postoperative inadequate analgesia.…”

“…[15,38,39] Recent genetic studies have identified rare and common mutations in SCN9A and SCN10A as contributory both in chronic pain conditions and postoperative pain. [15,16,39] Guangyou Duan et al reported that 3312G>T (SCN9A), a nonsynonymous SNP leading to the amino acid substitution V1104L in human Nav1.7, was associated with postoperative inadequate analgesia. [16] Patients carrying the 3312G allele had a higher incidence of inadequate analgesia than those carrying the 3312T allele.…”

“…In the present study, except for OPRM1, ABCB1, UGT2B7, and P2RX7, we selected other 14 genes known to be involved in systems related to pain perception and modulation based on evidence in the literature. The selected genes have been related to the ion channels (SCN9A, SCN10A, SCN11A, KCNJ6, TRPV1, and CACNA1E), [15][16][17][18][19][20] dopaminergic system (COMT, DRD2), [21,22] purinergic receptor (P2RY12),[23] adrenergic receptor (ADRB1), [24] estrogen receptor (ESR1), [25] serine/threonine kinase (TAOK3), [26] growth factors (TGFB1), [27] and transcription factor (CREB1). [28] The aim of the present study was to evaluate the association of common SNPs among aforementioned genes with the inadequate analgesia after single-port VATS.…”