Cregg R

University College London

ORCID Profile OpenAlex Profile
2
EM Publications
14
h-index
(1,115 citations, 36 total works)

Research Topics

Pain Mechanisms and Treatments (8) Ion channel regulation and function (5) Pain Management and Opioid Use (5) Anesthesia and Pain Management (4) Health, Medicine and Society (4)

Erythromelalgia Publications

Mexiletine as a treatment for primary erythromelalgia: normalization of biophysical properties of mutant L858F NaV 1.7 sodium channels.

Cregg R, Cox JJ, Bennett DL, Wood JN, Werdehausen R
British journal of pharmacology •

The non-selective sodium channel inhibitor mexiletine has been found to be effective in several animal models of chronic pain and has become popular in the clinical setting as an orally available alternative to lidocaine. It remains unclear why patients with monogenic pain disorders secondary to gain-of-function SCN9a mutations benefit from a low systemic concentration of mexiletine, which does not usually induce adverse neurological side effects. The aim of this study was, therefore, to investigate the biophysical effects of mexiletine on the L858F primary erythromelalgia NaV 1.7 mutation in vitro. Human wild-type and L858F-mutated NaV 1.7 channels were expressed in HEK293A cells. Whole-cell currents were recorded by voltage-clamp techniques to characterize the effect of mexiletine on channel gating properties. While the concentration-dependent tonic block of peak currents by mexiletine was similar in wild-type and L858F channels, phasic block was more pronounced in cells transfected with the L858F mutation. Moreover, mexiletine substantially shifted the pathologically-hyperpolarized voltage-dependence of steady-state activation in L858F-mutated channels towards wild-type values and the voltage-dependence of steady-state fast inactivation was shifted to more hyperpolarized potentials, leading to an overall reduction in window currents. Mexiletine has a normalizing effect on the pathological gating properties of the L858F gain-of-function mutation in NaV 1.7, which, in part, might explain the beneficial effects of systemic treatment with mexiletine in patients with gain-of-function sodium channel disorders.

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Novel mutations mapping to the fourth sodium channel domain of Nav1.7 result in variable clinical manifestations of primary erythromelalgia.

Cregg R, Laguda B, Werdehausen R, Cox JJ, Linley JE , et al.
Neuromolecular medicine •

We identified and clinically investigated two patients with primary erythromelalgia mutations (PEM), which are the first reported to map to the fourth domain of Nav1.7 (DIV). The identified mutations (A1746G and W1538R) were cloned and transfected to cell cultures followed by electrophysiological analysis in whole-cell configuration. The investigated patients presented with PEM, while age of onset was very different (3 vs. 61 years of age). Electrophysiological characterization revealed that the early onset A1746G mutation leads to a marked hyperpolarizing shift in voltage dependence of steady-state activation, larger window currents, faster activation kinetics (time-to-peak current) and recovery from steady-state inactivation compared to wild-type Nav1.7, indicating a pronounced gain-of-function. Furthermore, we found a hyperpolarizing shift in voltage dependence of slow inactivation, which is another feature commonly found in Nav1.7 mutations associated with PEM. In silico neuron simulation revealed reduced firing thresholds and increased repetitive firing, both indicating hyperexcitability. The late-onset W1538R mutation also revealed gain-of-function properties, although to a lesser extent. Our findings demonstrate that mutations encoding for DIV of Nav1.7 can not only be linked to congenital insensitivity to pain or paroxysmal extreme pain disorder but can also be causative of PEM, if voltage dependency of channel activation is affected. This supports the view that the degree of biophysical property changes caused by a mutation may have an impact on age of clinical manifestation of PEM. In summary, these findings extent the genotype-phenotype correlation profile for SCN9A and highlight a new region of Nav1.7 that is implicated in PEM.

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