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An autosomal dominant manner was reported to be
inherited by two large Chinese kindred with familial episodic pain. The
clinical presentation of familial episodic pain showed that pain syndrome type
3 is distinct to type 1 disorder in pain caused by TRPA1 mutations that has
distal rather proximal distribution. Pain arises in clusters, happens at end of
day and is generally triggered by illness and fatigue after exercise .Non
steroidal anti-inflammatory drugs relieved the pain. Neurological examination
is normal and there is no evidence of sensory loss .Missense mutations (Arg225Cys
and Ala808Gly) were revealed in a combination of linkage analysis and whole
exome sequencing in both Chinese pedigrees. hyper excitability of cells of
dorsal root ganglia, with increased peak current densities and enhanced action
potential ? ring after current injection were caused by these mutations
according to the findings of study. By contrast with the Leu811Pro mutation in
the Nav1.9 ion channel, which is associated with congenital insensitivity to
pain, these mutations do not result in a depolarising shift in the resting
membrane potential. Therefore, different mutations in Nav1.9—all resulting in
gain of function but with distinct biophysical characteristics—have opposite
effects on dorsal root ganglia cell excitability and the clinical phenotype.

Gene variants and risk of developing chronic
acquired pain syndromes

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After tissue inflammation or neural injury
polymorphisms in the genes encoding ion channels might affect  an individual’s susceptibility to, and
severity of, chronic pain. Testing this hypothesis has been challenging not
only because detailed pain phenotyping is needed but also   view of the number of patients required to
power such studies . Chronic pain is not a homogeneous occurrence, many
pathophysiological mechanisms can coexist in one individual, and experimental
pain models in man suggest that pain evoked by di? erent stimuli has a distinct
genetic basis. Indeed, evidence shows that speci? c polymorphisms in TRPV1 and
TRPA1 alter the pattern of somatosensory dysfunction on sensory testing and do
not alter neuropathic pain severity. A single nucleotide polymorphism (SNP) in
SCN9A is responsible for  an aminoacid
substitution of arginine to tryptophan (Arg1150Trp; rs6746030) in the Nav1.7
sodium channel, which enhances cell excitability of dorsal root ganglia. Reimann
and colleagues reported that the minor allele was associated with increased
pain in patients with osteoarthritis, sciatica, and phantom limb syndrome. This
finding was not replicated in a larger cohort with osteoarthritis nor in
patients with chronic widespread pain. CACNA2D3 encodes the ?2?3 subunit of the
voltage dependent calcium-channel complex. This gene has been implicated in
thermal pain-related behaviour in flies  and mice.84 In healthy volunteers, the rare
allele of an SNP in CACNA2D3 (rs6777055, located within an intron) was
associated with reduced acute thermal pain and diminished chronic pain after
lumbar discectomy (no replication studies have been done till date) KCNS1
encodes the voltage-gated potassium channel subunit Kv9.1, which is
electrically silent but can modify the function of other functional ? subunits.
Reduced expression of Kv9.1 results in neuronal hyperexcitability in rodent
models.In a cohort of human experimental pain models (ie, healthy controls) and
patients with neuropathic pain, an SNP in KCNS1 (rs734784), which resulted in
substitution of isoleucine for valine (Ile488Val), was associated with a
substantial increase in acute pain in controls and in patients with neuropathic
pain after radiculopathy or post amputation, although no effect was observed on
postmastectomy pain. These study findings  suggest that the premorbid pain threshold or
sensitivity to pain correlates positively with risk of chronic neuropathic pain
and that KCNS1 plays a part in this process. However, this hypothesis has yet
to be proven in a prospective cohort. In a black South African population with
HIV-associated sensory neuropathy,the SNP rs734784 was not associated with pain
intensity; however, several haplotypes of population-speci? c SNPs did
correlate  with pain intensity. CACNG2
encodes a protein that is included among the ? subunit of voltage-dependent
calcium channel family. However, this name is a misnomer; the functional role
of CACNG2 is as a type 1 transmembrane AMPA receptor regulatory peptide. This
protein regulates trafficking  of this
key receptor (for the excitatory neurotransmitter glutamate) to the synapse.
CACNG2 affects  susceptibility to chronic
pain after nerve injury in mice; in patients, an association was noted between
increased susceptibility to pain after mastectomy and the haplotype of three
intronic SNPs (rs4820242, rs2284015, and rs2284017).90 No replication studies
have been done till  date. P2RX7 is an
ATP-gated ionotropic receptor that is highly expressed on cells of the myeloid
lineage and plays  a role in cytokine
release.96 Activation leads to the opening of a channel for small
cations,followed  to a  larger non-selective pore. After nerve injury
mouse strains with a P2RX7 gene variant that impairs pore formation showed
reduced mechanical hypersensitivity .91 In human cohorts of osteoarthritis and
post-mastectomy pain, the SNP rs7958311, which causes a substitution of
arginine for histidine (Arg270His), is also linked to impaired pore formation
and was associated with a signi?cant reduction in chronic pain. In summary,
?ndings of several studies show an association between the risk or severity of
pain and polymorphisms in ion channels and associated proteins. However, these
initial ? dings must be regarded as preliminary because either they are not
supported by replication studies or these are 
awaited studies . Such replication in large, distinct, and well-de?ned
chronic pain states (eg, neuropathic pain vs osteoarthritis-related pain)
are  needed to establish whether
polymorphisms either confer risk or severity of chronic pain across a range of
disorders or are speci?c to particular causes of disease. Most of the  studies so far have used fairly rudimentary
phenotyping, such as a global rating of ongoing pain. Careful analysis of
symptom descriptors and quantitative sensory testing could reveal genetic
polymorphisms modulating speci?c patho physiological aspects of persistent
pain. As with many other human traits, the e?ect size of individual common
genetic polymorphisms on pain severity is likely to be small.97 For example, a
haplotype of P2RX7  is associated signi?
cantly with postmastectomy pain accounted for 4·5% of variance in the trait.
However, such an association provides biological insight that a particular gene
or pathway may be a potential therapeutic target.

Treatments for pain that target ion channels

There is an urgent need of new analgesics that are
eff ective for the treatment of chronic pain. Current agents that have activity
directed against ion channels (eg, GABApentinoids, carbamazepine, and
mexiletine) were not developed as analgesics but as antiepileptic or
antiarrhythmic drugs. Efficacy can not be predicted in individual patients and
none of them is highly efficacious.Mostly their sideeffects limit their
practice. Ion-channel genes are good candidates for novel analgesic targets:
the e? ect on pain, and the side-e? ects, can be predicted from the human
phenotype (eg, anosmia with Nav1.7 antagonists, gut dysmotility with Nav1.9
antagonists)ion channels are cell-membrane proteins and, hence, easily
accessible to drugs within the bloodstream. The process of discovering chemical
and antibody antagonists (eg, against Nav1.7 and Nav1.8) or agonists (eg, of
Nav1.9) has been enhanced greatly by construction of large molecule libraries,
by computer modelling of proteins, and by combinatorial chemistry. Nav1.7
antagonists are expected to ameliorate acute and in? ammatory pain, but their  role in neuropathic pain is  unknown. Human trials of Nav1.7 antagonists
are in progress,but the extent to which the ion channel will need to be blocked
is unknown. People who are haploinsu? 
cient for Nav1.7 have normal pain perception. The aim would be to block
hypersensitivity by reduction of primary a? erent drive rather than to  achieve complete insensitivity to noxious
stimuli, which could lead to self-injury. Nav1.8 antagonists have shown e?  cacy against neuropathic pain in rodents,
however human trials are awaited.Concer 
been raised regarding that  cardiac
arrhythmias might arise after blockade In a mouse model of nerve injury, loss
of the pacemaker potassium channel HCN2 within sensory neurons blocked
neuropathic pain. However, loss of HCN2 in mice within the CNS and the heart
leads to absence epilepsy and cardiac sinus dysrhythmia, respectively.
Ivabradine is an antagonist that has proven e?  cacy for treatment of angina  and blocks all four hyperpolarisation
activated cyclic nucleotide-gated potassium (HCN) channels. A known side-e? ect
of ivabradine is bradycardia (presumably due to antagonism of either HCN2 or
HCN4, or both) but we do not know if this e? ect will limit the usefulness of
ivabradine as an analgesic. A further interesting idea is to exploit selective
expression of TRPV1 in nociceptors: coapplication of a TRPV1 agonist and QX-314
(a polar-membraneimpermeant lidocaine derivative) enables entry of this molecule
into axons and produces pain-speci? c local anaesthesia in rodents.

Conclusions and future directions

Our knowledge of pain pathology has been improved by
the genetic basis of rare heritable human pain disorders and has highlighted
the key functions of ion channels expressed in nociceptors.Although unexpected
is  primacy of the three voltage-gated
sodium channels—Nav1.7, Nav1.8, and Nav1.9—in acute pain sensing. Polymorphisms
in mendelian pain genes might also establish the risk and severity of acquired
pain states, such as painful diabetic neuropathy or osteoarthritis. Application
of new sequencing technologies enabling whole exome or genome sequencing and
better clinical phenotyping of pain disorders is likely to enhance our
understanding of how genetic variants in ion channels are linked to the human
pain perception. Development of transgenic mouse models of human disease, and
studying the genetic basis of sensory function in rodents, will generate
important complementary data for human studies. Such large datasets need
integration and consolidation, and publicly accessible databases have now be en
established. Sensory neuronal di? erentiation protocols for human inducible
pluripotent stem cells provide an opportunity to study ion-channel dysfunction in
human sensory neurons and should be a potent technique for drug
discovery.This  knowledge, combined with
improved human experimental pain models and clinical trial design, can lead to  translate to better treatment for both
inherited and acquired chronic pain syndromes.

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