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The Journal of Neuroscience, August 18, 2004, 24(33):7353-7365; doi:10.1523/JNEUROSCI.1850-04.2004

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Behavioral/Systems/Cognitive
A Role for Proinflammatory Cytokines and Fractalkine in Analgesia, Tolerance, and Subsequent Pain Facilitation Induced by Chronic Intrathecal Morphine

Ian N. Johnston,¹ Erin D. Milligan,¹ Julie Wieseler-Frank,¹ Matthew G. Frank,¹ Varlin Zapata,¹ Jay Campisi,² Stephen Langer,³ David Martin,⁴ Paula Green,⁵ M. Fleshner,² Leslie Leinwand,³ Steven F. Maier,¹ and Linda R. Watkins¹

Departments of ¹Psychology, ²Integrative Physiology, and ³Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, Colorado 80309, ⁴Department of Pharmacology, Amgen, Thousand Oaks, California 91320, and ⁵Department of Neuroscience Research, GlaxoSmithKline, Harlow, Essex CM19 5AW, United Kingdom

The present experiments examined the role of spinal proinflammatory cytokines [interleukin-1 (IL-1)] and chemokines (fractalkine) in acute analgesia and in the development of analgesic tolerance, thermal hyperalgesia, and tactile allodynia in response to chronic intrathecal morphine. Chronic (5 d), but not acute (1 d), intrathecal morphine was associated with a rapid increase in proinflammatory cytokine protein and/or mRNA in dorsal spinal cord and lumbosacral CSF. To determine whether IL-1 release modulates the effects of morphine, intrathecal morphine was coadministered with intrathecal IL-1 receptor antagonist (IL-1ra). This regimen potentiated acute morphine analgesia and inhibited the development of hyperalgesia, allodynia, and analgesic tolerance. Similarly, intrathecal IL-1ra administered after the establishment of morphine tolerance reversed hyperalgesia and prevented the additional development of tolerance and allodynia. Fractalkine also appears to modulate the effects of intrathecal morphine because coadministration of morphine with intrathecal neutralizing antibody against the fractalkine receptor (CX3CR1) potentiated acute morphine analgesia and attenuated the development of tolerance, hyperalgesia, and allodynia. Fractalkine may be exerting these effects via IL-1 because fractalkine (CX3CL1) induced the release of IL-1 from acutely isolated dorsal spinal cord in vitro. Finally, gene therapy with an adenoviral vector encoding for the release of the anti-inflammatory cytokine IL-10 also potentiated acute morphine analgesia and attenuated the development of tolerance, hyperalgesia, and allodynia. Taken together, these results suggest that IL-1 and fractalkine are endogenous regulators of morphine analgesia and are involved in the increases in pain sensitivity that occur after chronic opiates.

Key words: proinflammatory cytokines; anti-inflammatory cytokines; hyperalgesia; allodynia; rats; interleukin-1; interleukin-10

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Received May 12, 2004; revised July 7, 2004; accepted July 8, 2004.

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