Experimental hypoglycemia is a human model of stress-induced hyperalgesia

Abstract

Hypoglycemia is a physiological stress that leads to the release of stress hormones, such as catecholamines and glucocorticoids, and proinflammatory cytokines. These factors, in euglycemic animal models, are associated with stress-induced hyperalgesia. The primary aim of this study was to determine whether experimental hypoglycemia in humans would lead to a hyperalgesic state. In 2 separate 3-day admissions separated by 1 to 3 months, healthy study participants were exposed to two 2-hour euglycemic hyperinsulinemic clamps or two 2-hour hypoglycemic hyperinsulinemic clamps. Thermal quantitative sensory testing and thermal pain assessments were measured the day before and the day after euglycemia or hypoglycemia. In contrast to prior euglycemia exposure, prior hypoglycemia exposure resulted in enhanced pain sensitivity to hot and cold stimuli as well as enhanced temporal summation to repeated heat-pain stimuli. These findings suggest that prior exposure to hypoglycemia causes a state of enhanced pain sensitivity that is consistent with stress-induced hyperalgesia. This human model may provide a framework for hypothesis testing and targeted, mechanism-based pharmacological interventions to delineate the molecular basis of hyperalgesia and pain susceptibility.

Conflict of interest statement

The authors have no conflicts of interest to declare.

Copyright © 2012. Published by Elsevier B.V.

Figures

Figure 1. Study Design

Subjects participated in two, 3-day protocols separated in time by 1 to 3 months. Subjects were randomized by admission to participate in either euglycemic (target blood glucose 5.0 mmol/l) hyperinsulinemic clamp studies or hypoglycemic (target blood glucose 2.8 mmol/l) hyperinsulinemic clamp studies on day 2. Cytokine and hormone levels were obtained at baseline and at 45 minute intervals during clamp sessions. Sensory testing was conducted on days 1 and 3 by investigators unaware of whether a subject was participating in the euglycemia or hypoglycemia protocol. Sensory testing included thermal detection and thermal pain detection thresholds and thermal temporal summation.

Figure 2. Thermal sensitivity increases after hypoglycemia

Effect of exposure to antecedent euglycemia (black circles) and antecedent hypoglycemia (white circles) on thermal detection thresholds and thermal pain detection thresholds.Panel A: Day 3 cold detection thresholds were similar after antecedent euglycemia and antecedent hypoglycemia. Panel B: There is a higher cold-pain detection threshold (increased sensitivity) after antecedent hypoglycemia. Panel C: There is a lower heat detection threshold (increased sensitivity) after antecedent hypoglycemia. Panel D: There is a lower heat-pain detection threshold (increased sensitivity) after antecedent hypoglycemia.

Figure 3. Temporal summation increases after hypoglycemia

Thermal temporal summation after exposure to antecedent euglycemia (black circles) and antecedent hypoglycemia (white circles). The initial and 10th stimuli pain scores during thermal temporal summation are reported. There were no differences in initial pain response to temporal summation between treatments. There was an increase in windup pain after antecedent hypoglycemia.

Figure 4. IL-6 and epinephrine correlate with temporal summation pain

In (A), there was a positive correlation between temporal summation (windup) pain and the change in interleukin-6 levels during hypoglycemia (r=0.49, P