Opioid receptor blockade prevents exercise-associated autonomic failure in humans

Sofiya Milman, James Leu, Harry Shamoon, Septimiu Vele, Ilan Gabriely, Sofiya Milman, James Leu, Harry Shamoon, Septimiu Vele, Ilan Gabriely

Abstract

Hypoglycemia and exercise both induce the release of β-endorphin, which plays an important role in the modulation of the autonomic response during subsequent events. Because opioid receptor (OR) blockade during antecedent hypoglycemia has been shown to prevent hypoglycemia-associated autonomic failure, we hypothesized that OR blockade during exercise would prevent exercise-associated autonomic failure (EAAF). We studied 8 healthy subjects on 2 consecutive days, each of whom participated in three different studies in random order. The protocol on day 1 involved one of the following: 1) two 90-min hyperinsulinemic-euglycemic clamps plus naloxone infusion (control); 2) two 90-min hyperinsulinemic-euglycemic clamps with exercise at 60% Vo(2max), plus naloxone infusion (N+); or 3) same protocol as in the N+ group, but with saline infusion only (N-). On day 2, all were studied with stepped hyperinsulinemic-hypoglycemic clamps, using hormone concentrations and glucose turnover as indicators of hypoglycemia counterregulation. Compared with control, N- studies resulted in significantly blunted epinephrine and norepinephrine responses to subsequent hypoglycemia. Conversely, the N+ group exhibited unimpaired hypoglycemia counterregulation, characterized by appropriate increases in epinephrine, norepinephrine, and endogenous glucose production. Thus, OR blockade with naloxone during antecedent exercise prevents the development of acute EAAF by improving the catecholamine responses and by restoring endogenous glucose production.

Trial registration: ClinicalTrials.gov NCT00678145.

Figures

FIG. 1.
FIG. 1.
Plasma glucose concentrations (day 2) at each glucose step (A) and glucose infusion rates (day 2) at each glucose step (B) in the N−, N+, and control studies. *P < 0.01 for N− vs. N+ and control.
FIG. 2.
FIG. 2.
Concentrations of plasma insulin (A) and plasma C-peptide (B) are shown on day 2 in the N−, N+, and control studies.
FIG. 3.
FIG. 3.
Concentrations of plasma epinephrine (A), norepinephrine (B), glucagon (C), and cortisol (D) are shown on day 2 at each glucose step in the N−, N+, and control studies. *P < 0.05 for N− vs. N+ and control.
FIG. 4.
FIG. 4.
EGP on day 2 averaged for the final 30 min of each glucose step in the N−, N+, and control studies. *P < 0.01 for N− vs. N+ and control.

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