The Effects of Lidocaine on Central Respiratory Neuron Activity and Nociceptive-Related Responses in the Brainstem–Spinal Cord Preparation of the Newborn Rat

Shakuo, Tomoharu; Lin, Shu; Onimaru, Hiroshi

doi:10.1213/ane.0000000000001205

Cited by 9 publications

(2 citation statements)

References 29 publications

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“…Some studies have found that high doses of lidocaine and its quaternary derivatives induce respiratory depression and the underlying mechanisms have been investigated. High doses of lidocaine (100–400 μM) decrease the C4 burst rate, eventually resulting in the complete cessation of respiratory rhythm, and decrease the burst duration and negative slope conductance of preinspiratory neurons (Shakuo et al, 2016). Takahashi et al (2016) reported that QX‐314 also decreases the C4 burst rate, amplitude, and slope during the initial rising phase and the action potentials of respiratory neurons with a half‐decay time of about 5 min.…”

Section: Discussionmentioning

confidence: 99%

The 14‐day repeated‐dose toxicity studies of a fixed‐dose combination, QXOH/levobupivacaine, via subcutaneous injection in mice

Gao

Zhang

Deng

et al. 2021

J of Applied Toxicology

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QXOH‐LB, a fixed‐dose combination (35 mM QXOH and 10 mM levobupivacaine) has been shown to induce a long duration of local anesthesia in animal efficacy testing, which indicates potential for postoperative pain management. In this study, we evaluated the potential toxicity of QXOH‐LB in NIH mice under the Guidance on the repeated‐dose toxicity published by the China Food and Drug Administration. Mice (n = 30 per sex per group) were subcutaneously injected 5, 10, 20 mg/kg QXOH‐LB, 5, 10, 20 mg/kg QXOH, and 5 mg/kg levobupivacaine (LB) once a day for 14 days with sacrifice of main study animals; remaining mice (n = 10 per sex per group) were monitored for an additional 4‐week recovery period. Mice in the 10 and 20 mg/kg QXOH, and 20 mg/kg QXOH‐LB died, which was considered due to excessive respiratory inhibition. The doses of 10 mg/kg QXOH‐LB and 5 mg/kg QXOH were well tolerated without any clinical signs of toxicity. Therefore, the no‐observed‐adverse‐effect level (NOAEL) of QXOH‐LB and QXOH was considered to be 10 and 5 mg/kg/day, respectively. In the dose range from 5 to 20 mg/kg, the exposure of QXOH and LB in QXOH‐LB was equal to each agent used alone at the same dose in NIH mice. There was no gender difference on exposure and no evidence of accumulation.

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Section: Discussionmentioning

confidence: 99%

The 14‐day repeated‐dose toxicity studies of a fixed‐dose combination, QXOH/levobupivacaine, via subcutaneous injection in mice

Gao

Zhang

Deng

et al. 2021

J of Applied Toxicology

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“…Dexmedetomidine and morphine inhibited slow ventral root potentials following ipsilateral dorsal root stimulation in newborn rat spinal cord preparation in vitro [10]. We recently reported that lidocaine depressed nociception-related responses at lower concentrations than those that induced respiratory depression [11]. However, there is no report regarding the effects of QX-314 and combined application of capsaicin on nociception-related responses in the above in vitro experimental model.…”

Section: Introductionmentioning

confidence: 96%

Effects of a Quaternary Lidocaine Derivative, QX-314, on Slow Ventral Root Potentials in Neonatal Rats

Onimaru¹

2016

Austin J Anesthesia and Analgesia

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The use of QX-314 (a quaternary derivative of lidocaine) in the clinical setting has been proposed to achieve the selective inhibition of nociceptors that express transient receptor potential vanilloid 1 (TRPV1) channels with fewer motor deficits. It has been established that slow ventral root potential induced by ipsilateral dorsal root stimulation in the isolated (typically lumbar) spinal cord of newborn rats reflects the nociceptive response. This in vitro experimental model is useful for assessing the actions of analgesics. However, there is no report regarding the effects of QX-314 and the combined application of capsaicin in the in vitro experimental model. Therefore, we examined the effects of extracellularly applied QX-314 and capsaicin on the spinal reflex response in spinal cord preparations from newborn rats. We found that co-application of QX-314 (1mM) and capsaicin (10µM) caused significant attenuation of the reflex response that continued after washout. We suggest that QX-314 passed into neurons in the reflex arc through TRPV1 channels activated by capsaicin. Our report further provides the basic neuronal mechanisms to support the clinical use of QX-314 that seems to be potentially expected for analgesic treatment.

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Inhibitory effects of eugenol on putative nociceptive response in spinal cord preparation isolated from neonatal rats

et al. 2018

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Eugenol is contained in several plants including clove and is thought to exert an analgesic effect. It has been suggested that the slow ventral root potential induced by ipsilateral dorsal root stimulation in the isolated (typically lumbar) spinal cord of newborn rats reflects the nociceptive response, and this in vitro experimental model is useful to assess the actions of analgesics. To further elucidate neuronal mechanisms of eugenol-induced analgesia, we examined the effects of extracellularly applied eugenol on the nociceptive spinal reflex response. To evaluate the effects of eugenol on putative nociceptive responses, the ipsilateral fifth lumbar (L5) dorsal root was stimulated using a glass suction electrode, and the induced reflex responses were recorded from the L5 and twelfth thoracic (Th12) ventral roots in spinal cord preparations (Th10-L5) from newborn rats (postnatal day 0-3). We found that eugenol (0.25-1.0 mM) caused dose-dependent attenuation of the reflex response and also depressed spontaneous ventral root activity. We also found that the slow ventral root potential was further divided into two components: initial and late components. A lower concentration of eugenol selectively depressed the late component. The inhibitory effects by 1.0 mM eugenol were not reversed by 10 µM capsazepine (TRPV1 antagonist) or 40 µM HC-030031 (TRPA1 antagonist). The depressive effect of eugenol on the reflex response was also confirmed by optical recordings using voltage-sensitive dye. Our report provides additional evidence on the basic neuronal mechanisms of eugenol to support its clinical use as a potential analgesic treatment.

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The Effects of Lidocaine on Central Respiratory Neuron Activity and Nociceptive-Related Responses in the Brainstem–Spinal Cord Preparation of the Newborn Rat

Cited by 9 publications

References 29 publications

The 14‐day repeated‐dose toxicity studies of a fixed‐dose combination, QXOH/levobupivacaine, via subcutaneous injection in mice

The 14‐day repeated‐dose toxicity studies of a fixed‐dose combination, QXOH/levobupivacaine, via subcutaneous injection in mice

Effects of a Quaternary Lidocaine Derivative, QX-314, on Slow Ventral Root Potentials in Neonatal Rats

Inhibitory effects of eugenol on putative nociceptive response in spinal cord preparation isolated from neonatal rats

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