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?-Conotoxins that differentially block sodium channels NaV1.1 through 1.8 identify those responsible for action potentials in sciatic nerve.

ABSTRACT: Voltage-gated sodium channels (VGSCs) are important for action potentials. There are seven major isoforms of the pore-forming and gate-bearing ?-subunit (Na(V)1) of VGSCs in mammalian neurons, and a given neuron can express more than one isoform. Five of the neuronal isoforms, Na(V)1.1, 1.2, 1.3, 1.6, and 1.7, are exquisitely sensitive to tetrodotoxin (TTX), and a functional differentiation of these presents a serious challenge. Here, we examined a panel of 11 ?-conopeptides for their ability to block rodent Na(V)1.1 through 1.8 expressed in Xenopus oocytes. Although none blocked Na(V)1.8, a TTX-resistant isoform, the resulting "activity matrix" revealed that the panel could readily discriminate between the members of all pair-wise combinations of the tested isoforms. To examine the identities of endogenous VGSCs, a subset of the panel was tested on A- and C-compound action potentials recorded from isolated preparations of rat sciatic nerve. The results show that the major subtypes in the corresponding A- and C-fibers were Na(V)1.6 and 1.7, respectively. Ruled out as major players in both fiber types were Na(V)1.1, 1.2, and 1.3. These results are consistent with immunohistochemical findings of others. To our awareness this is the first report describing a qualitative pharmacological survey of TTX-sensitive Na(V)1 isoforms responsible for propagating action potentials in peripheral nerve. The panel of ?-conopeptides should be useful in identifying the functional contributions of Na(V)1 isoforms in other preparations.

SUBMITTER: Wilson MJ

PROVIDER: S-EPMC3121861 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

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μ-Conotoxins that differentially block sodium channels NaV1.1 through 1.8 identify those responsible for action potentials in sciatic nerve.

Wilson Michael J MJ Yoshikami Doju D Azam Layla L Gajewiak Joanna J Olivera Baldomero M BM Bulaj Grzegorz G Zhang Min-Min MM

Proceedings of the National Academy of Sciences of the United States of America 20110607 25

Voltage-gated sodium channels (VGSCs) are important for action potentials. There are seven major isoforms of the pore-forming and gate-bearing α-subunit (Na(V)1) of VGSCs in mammalian neurons, and a given neuron can express more than one isoform. Five of the neuronal isoforms, Na(V)1.1, 1.2, 1.3, 1.6, and 1.7, are exquisitely sensitive to tetrodotoxin (TTX), and a functional differentiation of these presents a serious challenge. Here, we examined a panel of 11 μ-conopeptides for their ability to ...[more]

PMID: 21652775

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Project description:BACKGROUND:The number of patients operated on for total knee arthroplasty (TKA) is growing worldwide. Outpatient surgery is defined by a length of stay (LOS) in the hospital of less than 12?h. This can be limited for TKA, with the efficient management of pain and perioperative complications, such as blood loss, affecting a safe hospital discharge. Outpatient TKA with a suitable protocol, including multimodal measures, could improve the success rate of this procedure. Among the main measures, single-shot sciatic nerve block in association with continuous femoral nerve block for pain control needs to be evaluated in outpatient TKA. Furthermore, to promote the safety of the postoperative period and to accelerate rehabilitation, patients who undergo ambulatory TKA could be discharged to a rehabilitation center on the day of surgery to screen adverse events and to optimize the rehabilitation process. This study is designed to assess the benefits of sciatic nerve block in postoperative pain relief for outpatient TKA. METHODS/DESIGN:This randomized prospective controlled study will be conducted in the knee unit of the teaching hospital of the Nice university and will include 40 patients undergoing primary unilateral outpatient TKA, discharged the day of surgery to a private rehabilitation center for enhanced recovery after surgery, after a hospital stay of less than 12?h. Before surgery, all patients will receive a continuous femoral nerve block with 2?mg/ml ropivacaine 20?ml, and then patients will be randomly assigned to receive or not receive a single-shot sciatic nerve block with 2?mg/ml ropivacaine, 20?ml. The primary outcome measure is the success rate of outpatient TKA. This rate is defined by patients discharged from the hospital to a rehabilitation center the day of surgery with no re-hospitalization due to insufficient pain control before the fifth postoperative day. Secondary outcomes include the incidence of major and minor adverse events during the first five postoperative days and measurement of the quality of recovery using the Knee injury and Osteoarthritis Outcome Score and the new International Knee Society scores plus the Quality of Recovery-40 questionnaire. DISCUSSION:The assessment of anesthesia and rehabilitation protocols enabling major orthopedic surgery, such as TKA, is necessary. This randomized controlled study will address the hypothesis that a suitable multimodal protocol including sciatic nerve block could improve pain control and thus improve the success rate of outpatient TKA. TRIAL REGISTRATION:EudraCT, 2016-000226-19. Registered on 15 April 2016.

Dataset Information

?-Conotoxins that differentially block sodium channels NaV1.1 through 1.8 identify those responsible for action potentials in sciatic nerve.

Publications

μ-Conotoxins that differentially block sodium channels NaV1.1 through 1.8 identify those responsible for action potentials in sciatic nerve.

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