Voltage-gated ion channel Nav1.7 innervation in patients with idiopathic rectal hypersensitivity and paroxysmal extreme pain disorder (familial rectal pain)

Abstract Background: Mutations in the SCN9A gene cause chronic pain and pain insensitivity syndromes. We aimed to study clinical, genetic, and electrophysiological features of paroxysmal extreme pain disorder (PEPD) caused by a novel SCN9A mutation. Methods: Description of a 4-generation family suffering from PEPD with clinical, genetic and electrophysiological studies including patch clamp experiments assessing response to drug and temperature. Results: The family was clinically comparable to those reported previously with the exception of a favorable effect of cold exposure and a lack of drug efficacy including with carbamazepine, a proposed treatment for PEPD. A novel p.L1612P mutation in the Nav1.7 voltage-gated sodium channel was found in the four affected family members tested. Electrophysiologically the mutation substantially depolarized the steady–state inactivation curve (V1/2 from −61.8 ± 4.5 mV to −30.9 ± 2.2 mV, n = 4 and 7, P < 0.001), significantly increased ramp current (from 1.8% to 3.4%, n = 10 and 12) and shortened recovery from inactivation (from 7.2 ± 5.6 ms to 2.2 ± 1.5 ms, n = 11 and 10). However, there was no persistent current. Cold exposure reduced peak current and prolonged recovery from inactivation in wild-type and mutated channels. Amitriptyline only slightly corrected the steady–state inactivation shift of the mutated channel, which is consistent with the lack of clinical benefit. Conclusions: The novel p.L1612P Nav1.7 mutation expands the PEPD spectrum with a unique combination of clinical symptoms and electrophysiological properties. Symptoms are partially responsive to temperature but not to drug therapy. In vitro trials of sodium channel blockers or temperature dependence might help predict treatment efficacy in PEPD.

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What's in a name--familial rectal pain syndrome becomes paroxysmal extreme pain disorder

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp.2006.089664 ◽

2006 ◽

Vol 77 (11) ◽

pp. 1294-1295 ◽

Cited By ~ 23

Author(s):

C R Fertleman ◽

C D Ferrie

Keyword(s):

Pain Syndrome ◽

Pain Disorder ◽

Rectal Pain ◽

Extreme Pain

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Paroxysmal extreme pain disorder (previously familial rectal pain syndrome)

Yearbook of Neurology and Neurosurgery ◽

10.1016/s0513-5117(08)79022-7 ◽

2008 ◽

Vol 2008 ◽

pp. 130-131

Author(s):

A. Verma

Keyword(s):

Pain Syndrome ◽

Pain Disorder ◽

Rectal Pain ◽

Extreme Pain

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Paroxysmal extreme pain disorder (previously familial rectal pain syndrome)

Neurology ◽

10.1212/01.wnl.0000268065.16865.5f ◽

2007 ◽

Vol 69 (6) ◽

pp. 586-595 ◽

Cited By ~ 104

Author(s):

C. R. Fertleman ◽

C. D. Ferrie ◽

J. Aicardi ◽

N.A.F. Bednarek ◽

O. Eeg-Olofsson ◽

...

Keyword(s):

Pain Syndrome ◽

Pain Disorder ◽

Rectal Pain ◽

Extreme Pain

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Faculty Opinions recommendation of SCN9A mutations in paroxysmal extreme pain disorder: allelic variants underlie distinct channel defects and phenotypes.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1053986.505944 ◽

2006 ◽

Author(s):

Gavril Pasternak

Keyword(s):

Pain Disorder ◽

Allelic Variants ◽

Extreme Pain

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Transmitter and ion channel profiles of neurons in the primate abducens and trochlear nuclei

Brain Structure and Function ◽

10.1007/s00429-021-02315-7 ◽

2021 ◽

Author(s):

Ümit Suat Mayadali ◽

Jérome Fleuriet ◽

Michael Mustari ◽

Hans Straka ◽

Anja Kerstin Ellen Horn

Keyword(s):

Eye Movements ◽

Ion Channel ◽

Membrane Properties ◽

Receptor Subtype ◽

Receptor Subtypes ◽

Voltage Gated ◽

Calcium Ion Channels ◽

Cell Type Specific ◽

Transmitter Receptors ◽

Intrinsic Membrane Properties

AbstractExtraocular motoneurons initiate dynamically different eye movements, including saccades, smooth pursuit and vestibulo-ocular reflexes. These motoneurons subdivide into two main types based on the structure of the neuro-muscular interface: motoneurons of singly-innervated (SIF), and motoneurons of multiply-innervated muscle fibers (MIF). SIF motoneurons are thought to provoke strong and brief/fast muscle contractions, whereas MIF motoneurons initiate prolonged, slow contractions. While relevant for adequate functionality, transmitter and ion channel profiles associated with the morpho-physiological differences between these motoneuron types, have not been elucidated so far. This prompted us to investigate the expression of voltage-gated potassium, sodium and calcium ion channels (Kv1.1, Kv3.1b, Nav1.6, Cav3.1–3.3, KCC2), the transmitter profiles of their presynaptic terminals (vGlut1 and 2, GlyT2 and GAD) and transmitter receptors (GluR2/3, NMDAR1, GlyR1α) using immunohistochemical analyses of abducens and trochlear motoneurons and of abducens internuclear neurons (INTs) in macaque monkeys. The main findings were: (1) MIF and SIF motoneurons express unique voltage-gated ion channel profiles, respectively, likely accounting for differences in intrinsic membrane properties. (2) Presynaptic glutamatergic synapses utilize vGlut2, but not vGlut1. (3) Trochlear motoneurons receive GABAergic inputs, abducens neurons receive both GABAergic and glycinergic inputs. (4) Synaptic densities differ between MIF and SIF motoneurons, with MIF motoneurons receiving fewer terminals. (5) Glutamatergic receptor subtypes differ between MIF and SIF motoneurons. While NMDAR1 is intensely expressed in INTs, MIF motoneurons lack this receptor subtype entirely. The obtained cell-type-specific transmitter and conductance profiles illuminate the structural substrates responsible for differential contributions of neurons in the abducens and trochlear nuclei to eye movements.

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