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.