Elsevier

Brain, Behavior, and Immunity

Volume 22, Issue 8, November 2008, Pages 1178-1189
Brain, Behavior, and Immunity

Proinflammatory cytokines oppose opioid-induced acute and chronic analgesia

https://doi.org/10.1016/j.bbi.2008.05.004Get rights and content

Abstract

Spinal proinflammatory cytokines are powerful pain-enhancing signals that contribute to pain following peripheral nerve injury (neuropathic pain). Recently, one proinflammatory cytokine, interleukin-1, was also implicated in the loss of analgesia upon repeated morphine exposure (tolerance). In contrast to prior literature, we demonstrate that the action of several spinal proinflammatory cytokines oppose systemic and intrathecal opioid analgesia, causing reduced pain suppression. In vitro morphine exposure of lumbar dorsal spinal cord caused significant increases in proinflammatory cytokine and chemokine release. Opposition of analgesia by proinflammatory cytokines is rapid, occurring ⩽5 min after intrathecal (perispinal) opioid administration. We document that opposition of analgesia by proinflammatory cytokines cannot be accounted for by an alteration in spinal morphine concentrations. The acute anti-analgesic effects of proinflammatory cytokines occur in a p38 mitogen-activated protein kinase and nitric oxide dependent fashion. Chronic intrathecal morphine or methadone significantly increased spinal glial activation (toll-like receptor 4 mRNA and protein) and the expression of multiple chemokines and cytokines, combined with development of analgesic tolerance and pain enhancement (hyperalgesia, allodynia). Statistical analysis demonstrated that a cluster of cytokines and chemokines was linked with pain-related behavioral changes. Moreover, blockade of spinal proinflammatory cytokines during a stringent morphine regimen previously associated with altered neuronal function also attenuated enhanced pain, supportive that proinflammatory cytokines are importantly involved in tolerance induced by such regimens. These data implicate multiple opioid-induced spinal proinflammatory cytokines in opposing both acute and chronic opioid analgesia, and provide a novel mechanism for the opposition of acute opioid analgesia.

Introduction

Evidence has recently accrued that repeated morphine administration induces the release of the proinflammatory cytokine, interleukin-1β (IL-1β), which opposes morphine analgesia (Johnston et al., 2004, Shavit et al., 2005). This is generally believed to be due to a progressive activation of spinal cord glia in response to repeated morphine (Song and Zhao, 2001, Watkins et al., 2005). Whether the release of IL-1 or other such proinflammatory mediators within spinal cord also contributes to the opposition of acute morphine analgesia is currently unknown. Likewise, the mechanism(s) by which acute opioids may induce proinflammatory mediators is unknown. While nitric oxide (NO) induced p38 mitogen-activated protein kinase (MAPK) activation in microglia has been implicated in decreased analgesia following repeated morphine (Cui et al., 2006, Liu et al., 2006), no parallel information exists as to the acute effects of morphine.

The present series of experiments explores several questions regarding the spinal proinflammatory effects of morphine, the prototypical opioid. Firstly, is a proinflammatory response restricted to morphine, a 4,5-epoxymorphinan, versus may it be a more generalized response to opioids from other opioid structural classes? Secondly, how rapidly does opioid-induced proinflammatory cytokine responses occur and to what extent does this oppose opioid analgesia? Thirdly, what proinflammatory mediators are responsible for opposing acute and chronic opioid analgesia and do they oppose analgesia by altering morphine pharmacokinetics? Finally, are these proinflammatory mediators correlationally or causally linked with reductions in opioid analgesia? The present work seeks to address these questions firstly using a behavioral approach which tests the effects of antagonists of the proinflammatory mediators hypothesized to be involved in opposing opioid analgesia, and analyzes of mRNA and protein changes in response to acute and repeated opioids. In addition, the development of analgesic tolerance (loss of pain suppression following repeated opioid exposure), opioid-induced hyperalgesia (enhanced responsivity to radiant heat stimuli as a consequence of repeated opioid exposure) and opioid-induced allodynia (enhanced responsivity to touch/pressure stimuli as a consequence of repeated opioid exposure) is examined with respect to which proinflammatory products are mediating these chronic opioid-induced changes. Lastly, the pharmacological characteristics of the response are examined to clarify whether proinflammatory cytokines alter the analgesic efficacy of morphine by altering its pharmacokinetics.

Section snippets

Subjects

Pathogen-free adult male Sprague–Dawley rats (300–375 g; Harlan Labs, Madison, WI) were used in all experiments. Rats were housed in temperature (23 ± 3 °C) and light (12 h:2 h light:dark cycle; lights on at 0700) controlled rooms with standard rodent chow and water available ad libitum. All procedures were approved by the Institutional Animal Care and Use Committee of the University of Colorado at Boulder. Each study involves n = 6 per group.

Drugs

Morphine sulfate was kindly gifted by Mallinckrodt, Inc.

Experiment 1: intrathecal interleukin-1 receptor antagonist (IL-1ra) “unmasks” opioid analgesia

In all experiments, both hindpaw withdrawal and tailflick data were collected and were consistent in the results found. For simplicity, tailflick data are primarily shown (e.g. Fig. 1A). Examples of hindpaw data are presented in Fig. 1B for morphine, and statistical analyses incorporated into the text for each study. Intrathecal morphine (15 μg) analgesia dissipated by ∼100-min (Fig. 1A). At this time, intrathecal IL-1ra (100 μg), which blocks the actions of IL-1, unveiled further analgesia,

Discussion

These studies demonstrate the novel findings that, ⩽5 min after intrathecal opioids, endogenous IL-1 reduces morphine analgesia. Intrathecal morphine analgesia was reduced 8-fold by spinal IL-1. IL-1 is not the only spinal proinflammatory cytokine involved, as endogenous TNF-α and IL-6 exert similar effects. Spinal IL-1 also opposes systemic opioid analgesia. This effect is not limited to morphine, but rather occurs with the structurally dissimilar opioid, methadone, as well. Importantly,

Acknowledgments

This work was supported by an International Association for the Study of Pain International Collaborative grant, American Australian Association Merck Company Foundation Fellowship, National Health and Medical Research Council C.J. Martin Fellowship (ID 465423) and NIH Grants DA023132, DA015642, DA017670 and DE017782. Thanks to the Debra Berkelhammer, Dr. Sondra Bland, Dr. Jose Amat, Dr. Erin Milligan, Chris Altman, Todd Carlson, Anita Brzeski, Sonica Patel, Kaly Warner, Nicole Crysdale,

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