Proinflammatory cytokines oppose opioid-induced acute and chronic 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,
References (49)
Avoiding fallacies in nociceptive measurements
Pain
(1995)- et al.
Quantitative assessment of tactile allodynia in the rat paw
J. Neurosci. Methods
(1994) - et al.
Activation of p38 mitogen-activated protein kinase in spinal microglia mediates morphine antinociceptive tolerance
Brain Res.
(2006) - et al.
Methadone maintenance patients are cross-tolerant to the antinociceptive effects of morphine
Pain
(2001) - et al.
Herpes-simplex antigen in rabbit cerebrospinal fluid
Lancet
(1977) - et al.
Effects of vagotomy on lipopolysaccharide-induced brain interleukin-1beta protein in rats
Auton. Neurosci.
(2000) - et al.
A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia
Pain
(1988) - et al.
HIV-1 gp120 stimulates proinflammatory cytokine-mediated pain facilitation via activation of nitric oxide synthase-I (nNOS)
Pain
(2004) - et al.
Minocycline attenuates mechanical allodynia and proinflammatory cytokine expression in rat models of pain facilitation
Pain
(2005) - et al.
Inhibition of neuronal nitric oxide synthase antagonizes morphine antinociceptive tolerance by decreasing activation of p38 MAPK in the spinal microglia
Neurosci. Lett.
(2006)
A method for increasing the viability of the external portion of lumbar catheters placed in the spinal subarachnoid space of rats
J. Neurosci. Methods
Thermal hyperalgesia and mechanical allodynia produced by intrathecal administration of the human immunodeficiency virus-1 (HIV-1) envelope glycoprotein, gp120
Brain Res.
Interleukin-1 antagonizes morphine analgesia and underlies morphine tolerance
Pain
The involvement of glial cells in the development of morphine tolerance
Neurosci. Res.
Intrathecal interleukin-1 receptor antagonist in combination with soluble tumor necrosis factor receptor exhibits an anti-allodynic action in a rat model of neuropathic pain
Neuroscience
Acute peripheral inflammation induces moderate glial activation and spinal IL-1beta expression that correlates with pain behavior in the rat
Brain Res.
Cytokines and the central nervous system
Brain Res. Bull.
Glia: novel counter-regulators of opioid analgesia
Trends Neurosci.
p38 Mitogen-activated protein kinase inhibitor SB203580 reverses the antianalgesia induced by dextro-morphine or morphine in the mouse spinal cord
Eur. J. Pharmacol.
Nociceptive responses to high and low rates of noxious cutaneous heating are mediated by different nociceptors in the rat: electrophysiological evidence
Pain
Role of the CX3CR1/p38 MAPK pathway in spinal microglia for the development of neuropathic pain following nerve injury-induced cleavage of fractalkine
Brain. Behav. Immun.
Inhibition of spinal microglial cathepsin S for the reversal of neuropathic pain
Proc. Natl. Acad. Sci. USA
Glial activation and segmental upregulation of interleukin-1b (IL-1b) in the rat spinal cord after surgical incision
Neurochem. Res.
Effects of vagotomy on serum endotoxin, cytokines, and corticosterone after intraperitoneal lipopolysaccharide
Am. J. Physiol. Regul. Integr. Comp. Physiol.
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