Rapid Elevation of Plasma Interleukin-6 by Morphine Is Dependent on Autonomic Stimulation of Adrenal Gland

Abstract

Several studies have demonstrated that opioids regulate a number of immune cell functions either through direct mechanisms or through the modulation of central nervous system outputs. It has been previously shown that morphine increases serum interleukin-6 (IL-6) levels; however, the mechanism by which this effect is produced is unknown. In the present study, experiments were designed to address the potential role of central opioid receptors, peripheral autonomic ganglia, and activation of the adrenals in the elevation of plasma IL-6 after morphine administration. A rapid and significant (2-fold) increase in plasma IL-6 was observed after morphine administration (10 mg/kg s.c.) to rats. This effect of morphine peaked within 30 min and remained elevated for at least 2 h. Central microinjection of morphine (10 g/2 l i.c.v.) mimicked the effects of peripherally administered morphine and was completely blocked by naltrexone (10 mg/kg s.c.) pretreatment. Pretreatment with a ganglionic blocker, chlorisondamine (0.5 mg/kg i.p.), also blocked the elevation of IL-6 by morphine, suggesting a role of the autonomic nervous system. In adrenalectomized animals, morphine administration did not increase IL-6 levels, whereas in adrenal demedullated animals, the effect of morphine remained intact. Thus, the adrenal cortex may be a potential source of IL-6, because IL-6 mRNA has been localized in the adrenal gland. Collectively, these data suggest a unique mechanism by which stimulation of central opioid receptors results in the elevation of plasma IL-6 through autonomic activation specifically of the adrenal cortex.

Attenuation of Morphine Tolerance, Withdrawal-Induced Hyperalgesia, and Associated Spinal Inflammatory Immune Responses by Propentofylline in Rats

“…This suggests that an altered opioid system in these animals could be responsible for differences in morphine actions compared to that of wildtype animals. Similar to our findings, elevation of IL-6 was observed following central or peripheral administration of morphine (Houghtling and Bayer, 2002;Zubelewicz et al, 2000), and IL-6 is known to induce hyperalgesia (Arruda et al, 1998;Oka and Hori, 1999).…”

The effect of morphine upon DNA methylation in ten regions of the rat brain

“…The changes seen in Il6 in the pons may be in accordance with the modulating role that opioids have in inflammatory pathways 45 . Our observation of increased Il6 promoter methylation is in contrast to reports of increased secretion in acute response to morphine in the spinal cord 4 and plasma 46,47 . Notably, however, we also identified regional-specificity in Il6 methylation levels, and therefore the difference in measured methylation levels may represent alterations in cell composition, such as increased microglial infiltration.…”

Role of endogenous IL-6 in the neonatal expansion and functionality of Wistar rat pancreatic alpha cells

“…It has been suggested that the neonatal increase in plasma glucagon may be related to the stress of birth through activation of the sympathetic nervous system that results in the release of catecholamines [24], which are potent stimuli of glucagon release [25]. In addition, catecholamines elevate circulating IL-6 [26,27], and IL-6 has been proposed as a factor in the increase in alpha cell mass in diabetes [17]. However, our study did not detect any increase in blood IL-6 levels with birth, and to our knowledge it has not been previously reported.…”