Opioid neurotransmission modulates pain and negative affect during psychological stress.To determine whether these effects differ between men and women, the opioid receptor antagonist naltrexone or placebo was administered double-blind to 21 men and 22 women before they completed 30 minutes of difficult mental arithmetic. To heighten negative affect, participants received seven moderately noxious electric shocks during the math task, which were believed to be contingent upon performance. Before and after the math task, participants rated pain intensity and unpleasantness while their left hand was immersed in 2 o C water for up to 4 minutes. Anxiety, discouragement and anger were also rated before, during and after the math task. Tolerance of cold-induced pain was greater in men, whereas discouragement during the math task was greater in women. Opioid blockade did not influence ratings of negative affect, which increased in line with the intensity and unpleasantness of shock-induced pain. The intensity and unpleasantness of cold-induced pain increased after the math task only in women administered naltrexone.Within the naltrexone condition, pain ratings increased most in the most discouraged subjects. However, this relationship was absent in placebo recipients, implying that the hyperalgesic effect of psychological distress was tempered by opioid release. Greater stress-evoked discouragement in women than men may explain why cold-induced pain increased after the math task only in women administered naltrexone.

To determine whether stress-evoked release of endogenous opioids might account for hypoalgesia in major depressive disorder (MDD), the µ-opioid antagonist naltrexone (50 mg) or placebo was administered double-blind to 24 participants with MDD and to 31 non-depressed controls. Eighty minutes later participants completed a painful foot cold pressor test and, after a 5-minute interval, began a 25-minute arithmetic task interspersed with painful electric shocks. Ten minutes later participants completed a second cold pressor test. Negative affect was greater in participants with MDD than in non-depressed controls throughout the experiment, and increased significantly in both groups during mental arithmetic. Before the math task, naltrexone unmasked direct linear relationships between severity of depression, negative affect while resting quietly, and cold-induced pain in participants with MDD. In contrast, facilitatory effects of naltrexone on cold-and shock-induced pain were greatest in controls with the lowest depression scores. Naltrexone strengthened the relationship between negative affect and shock-induced pain during the math task, particularly in the depressed group, and heightened anxiety in both groups toward the end of the task. Thus, µ-opioid activity apparently masked a positive association between negative affect and pain in the most distressed participants. These findings suggest that psychological distress inhibits pain via stress-evoked release of opioid peptides in severe cases of MDD. In addition, tonic endogenous opioid neurotransmission could inhibit depressive symptoms and pain in people with low depression scores.

The effect of the opioid antagonist naltrexone on the relationship between blood pressure and pain was examined in 24 participants with major depressive disorder and 31 non-depressed controls, before and after 25 min of stressful mental arithmetic. Pain was induced by immersing the non-dominant foot in 2 degrees C ice-water for as long as possible or until 4 min had elapsed (the cold pressor test). Blood pressure was measured before each cold pressor test, and at 2-min intervals during mental arithmetic. In the group as a whole, neither depression nor naltrexone influenced blood pressure at any stage of the experiment. However, naltrexone disrupted an association between elevated resting blood pressure and low levels of pain in non-depressed controls, suggesting that endogenous opioid peptides are involved in blood pressure-mediated analgesia. Effects were similar when expressed in relation to blood pressure during psychological stress. In contrast to controls, blood pressure was unrelated to pain in depressed participants in the placebo condition. However, naltrexone unmasked an association between blood pressure and pain--those with highest blood pressure reported least cold-induced pain. Thus, endogenous opioids apparently masked an analgesic mechanism linking elevated blood pressure with reduced sensitivity to pain in participants with major depressive disorder. Noradrenergic mechanisms involved in active coping, stress-induced analgesia and baroreflexes might account for these findings.