Anomalous enhancement of resurgent Na<sup>+</sup> currents at high temperatures by SCN9A mutations underlies the episodic heat-enhanced pain in inherited erythromelalgia.
Neuroactive ligand-receptor interaction and NMDA receptor as well as GABA-related DEGs, SCN9A, and TRPV1 may modulate the process of response to pain in sheep.
Human loss or gain-of-function mutations in the gene encoding Na<sub>v</sub>1.7 channels (SCN9A) are associated with either absence of pain, as reported for congenital insensitivity to pain, or with exacerbation of pain, as reported for primary erythromelalgia and paroxysmal extreme pain disorder.
We investigated whether genetic polymorphisms in the candidate genes COMT, OPRM1, OPRD1, TAOK3, TRPA1, TRPV1, and SCN9A are contributing to experimental pain variability between children.
The NAT may play an important role in regulating human pain thresholds and is a potential candidate gene for individuals with chronic pain disorders that map to the SCN9A locus, such as Inherited Primary Erythromelalgia, Paroxysmal Extreme Pain Disorder and Painful Small Fibre Neuropathy, but who do not contain mutations in the sense gene.
This study demonstrated that several candidate and tag SCN9A SNPs were associated with hypersensitivity or hyposensitivity to basal experimental pain stimulation.
Recent studies have expanded this spectrum with gain-of-function SCN9A mutations in patients with small fiber neuropathy and in a new syndrome of pain, dysautonomia, and small hands and small feet (acromesomelia).
Missense substitutions of SCN9A, the gene encoding sodium channel NaV1.7, SCN10A, the gene encoding sodium channel NaV1.8, and SCN11A, the gene encoding sodium channel NaV1.9, produce gain-of-function changes that contribute to pain in many human painful disorders.
These data strongly suggest that pain perception in at least a subset of patients with IC/BPS is influenced by this polymorphism in the SCN9A voltage-gated sodium channel.
Patients carrying the SCN9A 3312Tallele presented with lower postoperative pain sensitivity in the presence of a similar surgical pain stimulus, and had a lower likelihood of developing inadequate analgesia than those carrying the 3312Gallele.
However, deleting SCN9A in both sensory and sympathetic neurons abolishes these pain sensations and recapitulates the pain-free phenotype seen in humans with SCN9A loss-of-function mutations.
A direct role of sodium channels in pain has recently been confirmed by establishing a monogenic link between SCN9A, the gene which encodes sodium channel Nav1.7, and pain disorders in humans, with gain-of-function mutations causing severe pain syndromes, and loss-of-function mutations causing congenital indifference to pain.
This led us to investigate whether single nucleotide polymorphisms (SNPs) in SCN9A were associated with differing pain perception in the general population.