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1.
J Physiol ; 598(15): 3239-3257, 2020 08.
Article in English | MEDLINE | ID: mdl-32415789

ABSTRACT

KEY POINTS: 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.


Subject(s)
Respiratory Hypersensitivity , Respiratory Insufficiency , Analgesics, Opioid , Animals , Fentanyl/toxicity , Hypoxia , Rats , Rats, Sprague-Dawley
2.
Pain Rep ; 3(3): e658, 2018 May.
Article in English | MEDLINE | ID: mdl-29922747

ABSTRACT

INTRODUCTION: Chronic metabotropic glutamate receptor activation in nociceptive afferents may upregulate A-Kinase Anchoring Protein 150 (AKAP150) expression and/or function. OBJECTIVES: To quantify transcriptional changes in AKAP150 expression and/or function after long-term mGluR5 agonist exposure, and identify transcriptional elements responsible. METHODS: Dorsal root ganglia (DRG) were dissected from Sprague-Dawley rats and cultured for biochemical analysis of AKAP150 expression after prolonged mGluR5 agonist exposure. Serum response factor (SRF) expression was knocked down through siRNA in cultures to demonstrate significance to AKAP150 upregulation. Serum response factor was also knocked down in vivo through intrathecal injections of specifically targeted oligonucleotides to demonstrate significance to hyperalgesic priming behavior in persistent mechanical hypersensitivity. RESULTS: Serum response factor and AKAP150 are coexpressed in TRPV1(+) DRG neurons in intact DRG. Prolonged mGluR5 agonist exposure increases SRF-dependent transcription and AKAP150 expression in a manner sensitive to protein kinase C inhibition and SRF knock down. Serum response factor in vivo knock down reduces mechanical hyperalgesic priming. CONCLUSION: Serum response factor transcription plays an important role in transcriptional upregulation of AKAP and hyperalgesic priming behavior, and may contribute to the increased role of AKAP150 in the transition from acute to chronic pain.

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