Method of countering respiratory depression via activation of neuronal heteromeric nicotinic acetylcholine receptors
A technology of acetylcholine receptors and respiratory depression, applied in the fields of respiratory diseases, nervous system diseases, anti-inflammatory agents, etc.
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Embodiment 1
[0097] Example 1 -Effects of co-administration of fentanyl and drugs targeting α4β2 nAChR in vivo using adult rats
[0098] Plethysmographic recordings from adult rats were used to examine coadministration of drugs targeting α4β2 nAChRs (A85380, rivancillin, NS9283) with fentanyl to determine whether it could significantly reduce OIRD levels and reduce fatal overdose. Simultaneously monitor the level of analgesia to assess whether there is an additive effect of nAChR-targeting drugs and fentanyl.
[0099] figure 1 is a schematic diagram of the experimental protocol (Ren (Ren) et al., 2015). Briefly, three nociceptive testing methods and sedation were performed in addition to the measurement of respiratory parameters. Righting reflex testing was initiated 6-10 min after opioid administration and continued until the animal awoke from fentanyl-induced sedation. Tail clamping began 12 minutes after the opioid infusion and was repeated every 4 minutes. When the animal regain...
Embodiment 2
[0112] Example 2 - First-aid efficacy of α4β2 nAChR-targeted drugs (A85380, rivancillin, or NS9283) for fentanyl-induced respiratory depression
[0113] In vivo experiments were performed to determine whether an α4β2 nAChR-targeted drug could be used as a first-aid intervention against severe fentanyl-induced respiratory depression and lethality. The data showed that all three drugs had some positive effects, with the full agonist A85380 showing the strongest effect.
[0114] The advantage over naloxone is the maintenance of analgesic effect. This regimen achieves significant respiratory depression following a 6-minute continuous infusion of fentanyl (60 μg / kg for 20 minutes) in one tail vein or lethal following a 1-minute bolus infusion (80 μg / kg for 1 minute) Sexual apnea. A bolus of α4β2-targeted drug or vehicle was then administered into another tail vein injection to assess the efficacy of rescue from respiratory depression.
[0115] It was determined whether intramu...
Embodiment 3
[0119] Example 3 -μ-opioids and Mechanistic investigation of the interplay of α4β2 nACh receptor activation in inspiratory neurons and XII motor neurons
[0120] Detection of Opioid Agents and α4β2 nAChR Targeting Drug Pairs Using Recordings of Neural Activity from In Vitro Agents and Whole-Cell Patch Recordings Mechanism of action of neurons and XII motor neurons. use for and XII motor neuron populations in medullary slice preparations that generate robust, rhythmic inspiratory activity (Funk, 2013). Sections of the medulla were cut at specific craniocaudal levels to expose and XII motor neuron populations (Ruangkittisakul et al., 2006). The use of infrared differential interference contrast microscopy provides clear visualization of neurons for the targeting of whole-cell patch electrodes.
[0121] Brainstem-spinal cord and medullary slice preparations were obtained from neonatal Sprague-Durer rats. Rats were anesthetized with methoxyflurane, brains were excised,...
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