Effraim PR

Yale New Haven Hospital

OpenAlex Profile
3
EM Publications
13
h-index
(570 citations, 28 total works)

Research Topics

Pain Mechanisms and Treatments (15) Ion channel regulation and function (5) Neuroscience and Neuropharmacology Research (4) Botulinum Toxin and Related Neurological Disorders (4) Ocular Surface and Contact Lens (3)

Erythromelalgia Publications

Stem cell-derived sensory neurons modelling inherited erythromelalgia: normalization of excitability.

Alsaloum M, Labau JIR, Liu S, Effraim PR, Waxman SG
Brain : a journal of neurology •

Effective treatment of pain remains an unmet healthcare need that requires new and effective therapeutic approaches. NaV1.7 has been genetically and functionally validated as a mediator of pain. Preclinical studies of NaV1.7-selective blockers have shown limited success and translation to clinical studies has been limited. The degree of NaV1.7 channel blockade necessary to attenuate neuronal excitability and ameliorate pain is an unanswered question important for drug discovery. Here, we utilize dynamic clamp electrophysiology and induced pluripotent stem cell-derived sensory neurons (iPSC-SNs) to answer this question for inherited erythromelalgia, a pain disorder caused by gain-of-function mutations in Nav1.7. We show that dynamic clamp can produce hyperexcitability in iPSC-SNs associated with two different inherited erythromelalgia mutations, NaV1.7-S241T and NaV1.7-I848T. We further show that blockade of approximately 50% of NaV1.7 currents can reverse neuronal hyperexcitability to baseline levels.

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Reverse pharmacogenomics: carbamazepine normalizes activation and attenuates thermal hyperexcitability of sensory neurons due to Na 1.7 mutation I234T.

Yang Y, Adi T, Effraim PR, Chen L, Dib-Hajj SD , et al.
British journal of pharmacology •

Pharmacotherapy for pain currently involves trial and error. A previous study on inherited erythromelalgia (a genetic model of neuropathic pain due to mutations in the sodium channel, Na 1.7) used genomics, structural modelling and biophysical and pharmacological analyses to guide pharmacotherapy and showed that carbamazepine normalizes voltage dependence of activation of the Na 1.7-S241T mutant channel, reducing pain in patients carrying this mutation. However, whether this approach is applicable to other Na channel mutants is still unknown. We used structural modelling, patch clamp and multi-electrode array (MEA) recording to assess the effects of carbamazepine on Na 1.7-I234T mutant channels and on the firing of dorsal root ganglion (DRG) sensory neurons expressing these mutant channels. In a reverse engineering approach, structural modelling showed that the I234T mutation is located in atomic proximity to the carbamazepine-responsive S241T mutation and that activation of Na 1.7-I234T mutant channels, from patients who are known to respond to carbamazepine, is partly normalized with a clinically relevant concentration (30 μM) of carbamazepine. There was significantly higher firing in intact sensory neurons expressing Na 1.7-I234T channels, compared with neurons expressing the normal channels (Na 1.7-WT). Pre-incubation with 30 μM carbamazepine also significantly reduced the firing of intact DRG sensory neurons expressing Na 1.7-I234T channels. Although the expected use-dependent inhibition of Na 1.7-WT channels by carbamazepine was confirmed, carbamazepine did not enhance use-dependent inhibition of Na 1.7-I234T mutant channels. These results support the utility of a pharmacogenomic approach to treatment of pain in patients carrying sodium channel variants. This article is part of a themed section on Recent Advances in Targeting Ion Channels to Treat Chronic Pain. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.12/issuetoc.

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Between fire and ice: refractory hypothermia and warmth-induced pain in inherited erythromelalgia.

Tham SW, Li L, Effraim P, Waxman S
BMJ case reports •

Inherited erythromelalgia (IEM) is a well-described pain disorder caused by mutations of sodium channel Na1.7, a peripheral channel expressed within dorsal root ganglion and the sympathetic ganglion neurons. Clinically, IEM is characterised by paroxysmal attacks of severe pain, usually in the distal extremities, triggered by warmth or exercise. Pain is not adequately treated by existing pharmacological agents. Individuals with IEM classically cool their limbs for relief, in some cases resulting in tissue injury. We describe a patient from a family with IEM due to the L858F mutation of Na1.7 who presented with refractory hypothermia due to overcooling. This presentation of refractory hypothermia necessitating warming strategies, complicated by severe warmth-induced pain, posed a substantial therapeutic challenge. We report our experience in overcoming hypothermia lasting 3 weeks in a child with IEM, discuss possible pathophysiological mechanisms underlying this unusual complication and suggest potential therapeutic interventions.

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