A role for proinflammatory cytokines and fractalkine in analgesia, tolerance, and subsequent pain facilitation induced by chronic intrathecal morphine.
The present experiments examined the role of spinal proinflammatory cytokines [interleukin-1beta (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.
Department of Psychology, University of Colorado, Boulder, Colorado 80309, USA.
Ian N
IN
Johnston
Erin D
ED
Milligan
Julie
J
Wieseler-Frank
Matthew G
MG
Frank
Varlin
V
Zapata
Jay
J
Campisi
Stephen
S
Langer
David
D
Martin
Paula
P
Green
M
M
Fleshner
Leslie
L
Leinwand
Steven F
SF
Maier
Linda R
LR
Watkins
D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000073883:CX3C Chemokine Receptor 1; D054428:Chemokine CX3CL1; D020523:Chemokines, CX3C / Q000494:pharmacology / Q000502:physiology*; D004361:Drug Tolerance; D015316:Genetic Therapy; D006358:Hot Temperature; D006930:Hyperalgesia / Q000276:immunology* / Q000628:therapy; D007249:Inflammation / Q000276:immunology; D007278:Injections, Spinal; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000096:biosynthesis / Q000134:cerebrospinal fluid / Q000502:physiology*; D016753:Interleukin-10 / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000494:pharmacology / Q000502:physiology*; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology*; D010146:Pain / Q000276:immunology; D059408:Pain Management; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018121:Receptors, Cytokine / Q000037:antagonists & inhibitors; D015728:Receptors, HIV / Q000037:antagonists & inhibitors; D012795:Sialoglycoproteins / Q000008:administration & dosage / Q000494:pharmacology; D013116:Spinal Cord / Q000187:drug effects / Q000276:immunology
D000701:Analgesics, Opioid; D000073883:CX3C Chemokine Receptor 1; D054428:Chemokine CX3CL1; D020523:Chemokines, CX3C; C515540:Cx3cl1 protein, rat; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D008565:Membrane Proteins; D012333:RNA, Messenger; D018121:Receptors, Cytokine; D015728:Receptors, HIV; D012795:Sialoglycoproteins; D016753:Interleukin-10; D009020:Morphine