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Intermittent hypercapnic hypoxia induces respiratory hypersensitivity to fentanyl accompanied by tonic respiratory depression by endogenous opioids.

ABSTRACT:

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Sleep apnoea increases susceptibility to opioid-induced respiratory depression (OIRD). Endogenous opioids are implicated as a contributing factor in sleep apnoea. Rats exposed to sleep-phase chronic intermittent hypercapnic hypoxia (CIHH) for 7 days exhibited exaggerated OIRD to systemic fentanyl both while anaesthetized and artificially ventilated and while conscious and breathing spontaneously, implicating heightened CNS inhibitory efficacy of fentanyl. CIHH also induced tonic endogenous opioid suppression of neural inspiration. Sleep-related episodes of hypercapnic hypoxia, as in sleep apnoea, promote hypersensitivity to OIRD, with tonic respiratory depression by endogenous opioids implicated as a potential underlying cause.

Abstract

Sleep apnoea (SA) increases opioid-induced respiratory depression (OIRD) and lethality. To test the hypothesis that this results from chronic intermittent bouts of hypercapnic hypoxia (CIHH) accompanying SA, we compared OIRD across continuously normoxic control rats and rats exposed to sleep-phase (8 h/day) CIHH for 1 week. OIRD sensitivity was first assessed in anaesthetized (urethane/α-chloralose), vagotomized and artificially ventilated rats by recording phrenic nerve activity (PNA) to index neural inspiration and quantify PNA burst inhibition to graded doses (0, 2, 20, 50 μg kg^-1 , i.v.) of the synthetic opioid fentanyl. Fentanyl dose-dependently reduced PNA burst frequency (P = 0.0098-0.0001), while increasing the duration of burst quiescence at 50 μg kg^-1 (P < 0.0001, n = 5-6/group/dose). CIHH shifted the fentanyl dose-phrenic burst frequency response curve to the left (P = 0.0163) and increased the duration of burst quiescence (P < 0.0001). During fentanyl recovery, PNA burst width was increased relative to baseline in normoxic and CIHH rats. Systemic naloxone (1 mg kg^-1 , i.v.) reversed fentanyl-induced PNA arrest in both groups (P = 0.0002), and increased phrenic burst amplitude above baseline (P = 0.0113) in CIHH rats only. Differential sensitivity to anaesthesia as a cause of CIHH-related OIRD hypersensitivity was excluded by observing in conscious spontaneously breathing rats that fentanyl at 20 μg kg^-1 (i.v.), which silenced PNA in anaesthetized rats, differentially increased breathing variability in normoxic versus CIHH rats (P = 0.0427), while significantly reducing breathing frequency (P < 0.0001) and periodicity (P = 0.0003) in CIHH rats only. Findings indicate that CIHH increased OIRD sensitivity, with tonic inspiratory depression by endogenous opioids as a likely contributing cause.

SUBMITTER: Brackley AD

PROVIDER: S-EPMC8162062 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:RationaleAcute intermittent hypoxia (AIH) is a promising strategy to induce functional motor recovery following chronic spinal cord injuries and neurodegenerative diseases. Although significant results are obtained, human AIH trials report considerable inter-individual response variability.ObjectivesIdentify individual factors ( e.g. , genetics, age, and sex) that determine response magnitude of healthy adults to an optimized AIH protocol, acute intermittent hypercapnic-hypoxia (AIHH).MethodsAssociations of individual factors with the magnitude of AIHH (15, 1-min O 2 =9.5%, CO 2 =5% episodes) induced changes in diaphragm motor-evoked potential amplitude (MEP) and inspiratory mouth occlusion pressures (P 0.1 ) were evaluated in 17 healthy individuals (age=27±5 years) compared to Sham. Single nucleotide polymorphisms (SNPs) in genes linked with mechanisms of AIH induced phrenic motor plasticity ( BDNF, HTR 2A , TPH 2 , MAOA, NTRK 2 ) and neuronal plasticity (apolipoprotein E, APOE ) were tested. Variations in AIHH induced plasticity with age and sex were also analyzed. Additional experiments in humanized ( h ) ApoE knock-in rats were performed to test causality.ResultsAIHH-induced changes in diaphragm MEP amplitudes were lower in individuals heterozygous for APOE 4 ( i.e., APOE 3/4 ) allele versus other APOE genotypes (p=0.048). No significant differences were observed between any other SNPs investigated, notably BDNFval/met ( all p>0.05 ). Males exhibited a greater diaphragm MEP enhancement versus females, regardless of age (p=0.004). Age was inversely related with change in P 0.1 within the limited age range studied (p=0.007). In hApoE 4 knock-in rats, AIHH-induced phrenic motor plasticity was significantly lower than hApoE 3 controls (p<0.05).ConclusionsAPOE 4 genotype, sex and age are important biological determinants of AIHH-induced respiratory motor plasticity in healthy adults.Addition to knowledge baseAcute intermittent hypoxia (AIH) is a novel rehabilitation strategy to induce functional recovery of respiratory and non-respiratory motor systems in people with chronic spinal cord injury and/or neurodegenerative diseases. Since most AIH trials report considerable inter-individual variability in AIH outcomes, we investigated factors that potentially undermine the response to an optimized AIH protocol, acute intermittent hypercapnic-hypoxia (AIHH), in healthy humans. We demonstrate that genetics (particularly the lipid transporter, APOE ), age and sex are important biological determinants of AIHH-induced respiratory motor plasticity.

Project description:RationaleAcute intermittent hypoxia (AIH) shows promise for enhancing motor recovery in chronic spinal cord injuries and neurodegenerative diseases. However, human trials of AIH have reported significant variability in individual responses.ObjectivesIdentify individual factors (eg, genetics, age, and sex) that determine response magnitude of healthy adults to an optimized AIH protocol, acute intermittent hypercapnic-hypoxia (AIHH).MethodsIn 17 healthy individuals (age = 27 ± 5 yr), associations between individual factors and changes in the magnitude of AIHH (15, 1-min O2 = 9.5%, CO2 = 5% episodes) induced changes in diaphragm motor-evoked potential (MEP) amplitude and inspiratory mouth occlusion pressures (P0.1) were evaluated. Single nucleotide polymorphisms (SNPs) in genes linked with mechanisms of AIH induced phrenic motor plasticity (BDNF, HTR2A, TPH2, MAOA, NTRK2) and neuronal plasticity (apolipoprotein E, APOE) were tested. Variations in AIHH induced plasticity with age and sex were also analyzed. Additional experiments in humanized (h)ApoE knock-in rats were performed to test causality.ResultsAIHH-induced changes in diaphragm MEP amplitudes were lower in individuals heterozygous for APOE4 (i.e., APOE3/4) compared to individuals with other APOE genotypes (P = 0.048) and the other tested SNPs. Males exhibited a greater diaphragm MEP enhancement versus females, regardless of age (P = 0.004). Additionally, age was inversely related with change in P0.1 (P = 0.007). In hApoE4 knock-in rats, AIHH-induced phrenic motor plasticity was significantly lower than hApoE3 controls (P < 0.05).ConclusionsAPOE4 genotype, sex, and age are important biological determinants of AIHH-induced respiratory motor plasticity in healthy adults.Addition to knowledge baseAIH is a novel rehabilitation strategy to induce functional recovery of respiratory and non-respiratory motor systems in people with chronic spinal cord injury and/or neurodegenerative disease. Figure 5 Since most AIH trials report considerable inter-individual variability in AIH outcomes, we investigated factors that potentially undermine the response to an optimized AIH protocol, AIHH, in healthy humans. We demonstrate that genetics (particularly the lipid transporter, APOE), age and sex are important biological determinants of AIHH-induced respiratory motor plasticity.

Project description:PurposeSince the appearance of fentanyl followed by its many kinds of analogues around 1988, North America has been exposed to fierce synthetic opioid pandemic resulting in more than 130,000 deaths due to their overdoses until May 2019, when China declared to prohibit the licit fentanyl analog production. However, the Chinese announcement did not go into force in USA due to the adroit strategies of tough traffickers. Thus, contrary to the expectation, the number of synthetic opioid products and their poisoning cases in USA has increased by about 30%; especially, various benzimidazole synthetic opioids have revived on the illicit drug market during a recent few years. In this article, the recent abrupt changes in the situations of illicit synthetic opioid market and their current abuses are described.MethodsVarious databases, such as SciFinder, Google, and Google Scholar, were utilized to collect relevant reports referring old but newly appearing synthetic opioids.ResultsAt the present time, there are several families of new synthetic opioids, which are not fentanyl derivatives; MT-45 and its analogs, benzamide and 2-phenylacetamide opioids (U-series opioids), and benzimidazole opioids. Most of the above substances had been developed in 1950s to 1970s, but had never been used as analgesic medicines, because of their severe adverse effects, such as respiratory depression, physical dependence, and resulting deaths. However, there is possibility that these drugs will become main illicit synthetic opioids in place of the fentanyl analogs during coming several years from this time.ConclusionsAll of the above non-fentanyl-derived families had been developed 50-70 years ago to establish them as analgesic medicines, but had been unsuccessful. These drugs largely appeared in the illicit drug markets in North America, Europe, and Australia, during recent years. Pharmacological, toxicological, and metabolic studies are insufficient for benzamide and 2-phenylacetamide opioids, and are very scant especially for benzimidazole opioids. This time we should start studying pharmacotoxicology of the newly emerging synthetic opioids to alert forensic toxicologists in the world and to suppress their rapid and wide spread in the world.Supplementary informationThe online version contains supplementary material available at 10.1007/s11419-022-00624-y.

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Intermittent hypercapnic hypoxia induces respiratory hypersensitivity to fentanyl accompanied by tonic respiratory depression by endogenous opioids.

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