Activation of μ‐opioid receptors in the rostral ventrolateral medulla blocks the sympathetic counter‐regulatory response to glucoprivation

Abstract

Intensive insulin therapy is the gold standard for managing serum glucose levels in patients with insulin‐deficient diabetes mellitus. Hypoglycaemia‐associated autonomic failure (HAAF) is a clinical syndrome characterised by the absence of a glucose counter‐regulatory response to hypoglycaemia or glucoprivation. The precise physiologic mechanisms underlying HAAF remain unknown. Recent data from human studies suggests activation of the endogenous opioid system during antecedent hypoglycaemia may contribute to unawareness of hypoglycaemia.Here, we aimed to determine whether or not activation of rostral ventrolateral medullary (RVLM) μ‐opioid receptors results in downstream sympathoinhibition, resulting in attenuated glucose production, and an impaired counter‐regulatory response following glucoprivation. Experiments were performed in sodium pentobarbital anaesthetised (65 mg/kg) male Sprague‐Dawley rats (250–350g).Bilateral activation of RVLM μ‐opioid receptors with DAMGO (8 mM, 50 nl) caused depression of adrenal sympathetic nerve activity (ASNA), that lasted at least 60 minutes (Δ−56.9 ± 9.8% vs saline: Δ1.7 ± 4.4%, P<0.05). In parallel, blood glucose levels were also reduced (Δ−0.8 ± 0.2 mM vs saline: Δ0.2 ± 0.3 mM, P<0.05). The counter‐regulatory response to glucoprivation (measured by ASNA efferent activity) induced by 2‐deoxyglucose was completely attenuated 60 minutes following DAMGO microinjections (Δ−4.4 ± 0.7% vs saline+2‐DG: Δ59.6 ± 8.0%, P<0.05). Bilateral μ‐opioid receptor activation also caused a significant decrease in mean arterial pressure (Δ−28.7 ± 6.1 mmHg vs saline: Δ−9.9 ± 7.3 mmHg, P<0.05) and heart rate (Δ−40.4 ± 14.9 bpm vs saline: Δ−11.1 ± 9.7 bpm, P<0.05).In conclusion, activation of RVLM μ‐opioid receptors reproduces features of HAAF (attenuated neural efferent response to glucoprivation). The mechanism underlying HAAF may include activation of RVLM μ‐opioid receptors to facilitate sympathoinhibition. Coupled with this sympathoinhibition, the reduced blood glucose levels may contribute to HAAF by increasing the threshold to elicit counter‐regulatory response.Support or Funding InformationNational Health and Medical Research Council of Australia, The University of Sydney, The Heart Research InstituteThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.