Dataset Information

Bupivacaine-induced cellular entry of QX-314 and its contribution to differential nerve block.

ABSTRACT:

Background and purpose

Selective nociceptor fibre block is achieved by introducing the cell membrane impermeant sodium channel blocker lidocaine N-ethyl bromide (QX-314) through transient receptor potential V1 (TRPV1) channels into nociceptors. We screened local anaesthetics for their capacity to activate TRP channels, and characterized the nerve block obtained by combination with QX-314.

Experimental approach

We investigated TRP channel activation in dorsal root ganglion (DRG) neurons by calcium imaging and patch-clamp recordings, and cellular QX-314 uptake by MS. To characterize nerve block, compound action potential (CAP) recordings from isolated nerves and behavioural responses were analysed.

Key results

Of the 12 compounds tested, bupivacaine was the most potent activator of ruthenium red-sensitive calcium entry in DRG neurons and activated heterologously expressed TRPA1 channels. QX-314 permeated through TRPA1 channels and accumulated intracellularly after activation of these channels. Upon sciatic injections, QX-314 markedly prolonged bupivacaine's nociceptive block and also extended (to a lesser degree) its motor block. Bupivacaine's blockade of C-, but not A-fibre, CAPs in sciatic nerves was extended by co-application of QX-314. Surprisingly, however, this action was the same in wild-type, TRPA1-knockout and TRPV1/TRPA1-double knockout mice, suggesting a TRP-channel independent entry pathway. Consistent with this, high doses of bupivacaine promoted a non-selective, cellular uptake of QX-314.

Conclusions and implications

Bupivacaine, combined with QX-314, produced a long-lasting sensory nerve block. This did not require QX-314 permeation through TRPA1, although bupivacaine activated these channels. Regardless of entry pathway, the greatly extended duration of block produced by QX-314 and bupivacaine may be clinically useful.

SUBMITTER: Brenneis C

PROVIDER: S-EPMC3904263 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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Publications

Bupivacaine-induced cellular entry of QX-314 and its contribution to differential nerve block.

Brenneis C C Kistner K K Puopolo M M Jo S S Roberson Dp D Sisignano M M Segal D D Cobos E J EJ Wainger B J BJ Labocha S S Ferreirós N N von Hehn C C Tran J J Geisslinger G G Reeh P W PW Bean B P BP Woolf C J CJ

British journal of pharmacology 20140101 2

<h4>Background and purpose</h4>Selective nociceptor fibre block is achieved by introducing the cell membrane impermeant sodium channel blocker lidocaine N-ethyl bromide (QX-314) through transient receptor potential V1 (TRPV1) channels into nociceptors. We screened local anaesthetics for their capacity to activate TRP channels, and characterized the nerve block obtained by combination with QX-314.<h4>Experimental approach</h4>We investigated TRP channel activation in dorsal root ganglion (DRG) ne ...[more]

PMID: 24117225

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Project description:BackgroundCurrently available local anesthetics approved for single-injection peripheral nerve blocks have a maximum duration of <24 hours. A liposomal bupivacaine formulation (EXPAREL, Pacira Pharmaceuticals, Inc., San Diego, CA), releasing bupivacaine over 96 hours, recently gained Food and Drug Administration approval exclusively for wound infiltration but not peripheral nerve blocks.MethodsBilateral single-injection femoral nerve blocks were administered in healthy volunteers (n = 14). For each block, liposomal bupivacaine (0-80 mg) was mixed with normal saline to produce 30 mL of study fluid. Each subject received 2 different doses, 1 on each side, applied randomly in a double-masked fashion. The end points included the maximum voluntary isometric contraction (MVIC) of the quadriceps femoris muscle and tolerance to cutaneous electrical current in the femoral nerve distribution. Measurements were performed from baseline until quadriceps MVIC returned to 80% of baseline bilaterally.ResultsThere were statistically significant dose responses in MVIC (0.09%/mg, SE = 0.03, 95% confidence interval [CI], 0.04-0.14, P = 0.002) and tolerance to cutaneous current (-0.03 mA/mg, SE = 0.01, 95% CI, -0.04 to -0.02, P < 0.001), however, in the opposite direction than expected (the higher the dose, the lower the observed effect). This inverse relationship is biologically implausible and most likely due to the limited sample size and the subjective nature of the measurement instruments. While peak effects occurred within 24 hours after block administration in 75% of cases (95% CI, 43%-93%), block duration usually lasted much longer: for bupivacaine doses >40 mg, tolerance to cutaneous current did not return to within 20% above baseline until after 24 hours in 100% of subjects (95% CI, 56%-100%). MVIC did not consistently return to within 20% of baseline until after 24 hours in 90% of subjects (95% CI, 54%-100%). Motor block duration was not correlated with bupivacaine dose (0.06 hour/mg, SE = 0.14, 95% CI, -0.27 to 0.39, P = 0.707).ConclusionsThe results of this investigation suggest that deposition of a liposomal bupivacaine formulation adjacent to the femoral nerve results in a partial sensory and motor block of >24 hours for the highest doses examined. However, the high variability of block magnitude among subjects and inverse relationship of dose and response magnitude attests to the need for a phase 3 study with a far larger sample size, and that these results should be viewed as suggestive, requiring confirmation in a future trial.

Project description:BackgroundDexamethasone has been studied as an effective adjuvant to prolong the analgesia duration of local anesthetics in peripheral nerve block. However, the route of action for dexamethasone and its potential neurotoxicity are still unclear.MethodsA mouse sciatic nerve block model was used. The sciatic nerve was injected with 60ul of combinations of various medications, including dexamethasone and/or bupivacaine. Neurobehavioral changes were observed for 2 days prior to injection, and then continuously for up to 7 days after injection. In addition, the sciatic nerves were harvested at either 2 days or 7 days after injection. Toluidine blue dyeing and immunohistochemistry test were performed to study the short-term and long-term histopathological changes of the sciatic nerves. There were six study groups: normal saline control, bupivacaine (10mg/kg) only, dexamethasone (0.5mg/kg) only, bupivacaine (10mg/kg) combined with low-dose (0.14mg/kg) dexamethasone, bupivacaine (10mg/kg) combined with high-dose (0.5mg/kg) dexamethasone, and bupivacaine (10mg/kg) combined with intramuscular dexamethasone (0.5mg/kg).ResultsHigh-dose perineural dexamethasone, but not systemic dexamethasone, combined with bupivacaine prolonged the duration of both sensory and motor block of mouse sciatic nerve. There was no significant difference on the onset time of the sciatic nerve block. There was "rebound hyperalgesia" to thermal stimulus after the resolution of plain bupivacaine sciatic nerve block. Interestingly, both low and high dose perineural dexamethasone prevented bupivacaine-induced hyperalgesia. There was an early phase of axon degeneration and Schwann cell response as represented by S-100 expression as well as the percentage of demyelinated axon and nucleus in the plain bupivacaine group compared with the bupivacaine plus dexamethasone groups on post-injection day 2, which resolved on post-injection day 7. Furthermore, we demonstrated that perineural dexamethasone, but not systemic dexamethasone, could prevent axon degeneration and demyelination. There was no significant caspase-dependent apoptosis process in the mouse sciatic nerve among all study groups during our study period.ConclusionsPerineural, not systemic, dexamethasone added to a clinical concentration of bupivacaine may not only prolong the duration of sensory and motor blockade of sciatic nerve, but also prevent the bupivacaine-induced reversible neurotoxicity and short-term "rebound hyperalgesia" after the resolution of nerve block.

Project description:Objective The interscalene brachial plexus block (ISBB) constitutes the gold standard for analgesia after shoulder procedures. Ipsilateral phrenic nerve block remains the most common adverse effect after ISBB. Alternative nerve blocks are performed in shoulder surgery in order to prevent hemi-diaphragmatic paralysis (HDP). The purpose of the present study was to investigate the minimum effective local anesthetic volume of 0.5% bupivacaine for postoperative analgesia with an anterior suprascapular nerve block (ASSB). The secondary aim was to investigate diaphragm functions with the local anesthetic doses used while conducting effective volume research. Method This prospective observational study was conducted at the American Hospital of Istanbul, Turkey, from March to July 2022. The initial injected volume of 0.5% bupivacaine was 10 ml. Our clinical experience indicates that this yields a complete sensory block of the anterior suprascapular nerve. In accordance with the up-and-down method, the volume of 0.5% bupivacaine used for a particular patient was determined by the outcome of the preceding block, which represented block success. In case of effective ASSB being achieved, the volume of 0.5% bupivacaine to be administered to the next patient was lowered by 1 ml. In case of block failure, however, the volume of 0.5% bupivacaine to be applied in the subsequent case was increased by 1 ml. Ipsilateral hemi-diaphragmatic movement measurements were taken before (baseline) and 30 minutes after the block. General anesthesia was induced 60 minutes after the completion of the block performance by means of a standardized protocol. Results Sixty-seven patients were included in the study. The ED50 and ED95 calculated for anterior suprascapular nerve block using probit transformation and logistic regression analysis were 2.646 (95% CI, 0.877-2.890) and 3.043 ml (95% CI, 2.771-4.065), respectively. When complete paralysis was defined as 75% or above, partial paralysis as 25-50%, and no paralysis as 25% or less, volumes of 6 ml or lower appeared to cause no paralysis for the anterior suprascapular nerve block. Conclusion We, therefore, recommend using a volume of 6 ml or less in order to achieve diaphragm-sparing features for anterior suprascapular nerve blocks.

Dataset Information

Bupivacaine-induced cellular entry of QX-314 and its contribution to differential nerve block.

Background and purpose

Experimental approach

Key results

Conclusions and implications

Publications

Bupivacaine-induced cellular entry of QX-314 and its contribution to differential nerve block.

Similar Datasets

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