Proinflammatory cytokines oppose opioid-induced acute and chronic analgesia

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 minutes 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.

Morphine enhances IL-1β release through toll-like receptor 4-mediated endocytic pathway in microglia

“…P2X4 signaling may play a critical role in the inflammatory responses in the neuropathic pain [2]. P2X4R activation has been suggested to mediate IL-1β released in microglia [35].…”

“…Microglial activation is one of the most important mechanisms for morphine tolerance and hyperalgesia [1]. Activated microglia are a source of proinflammatory cytokines such as interleukin-1β (IL-1β) which may weaken morphine analgesia and contributes to the development of morphine tolerance [2].…”

Toll-like receptor 4-mediated nuclear factor-κB activation in spinal cord contributes to chronic morphine-induced analgesic tolerance and hyperalgesia in rats

“…Chronic administration of morphine also results in pain-related activation of neurons and glia, and induces the release of pro-infl ammatory cytokines and chemokines [15][16][17] . The prevailing evidence shows that acute and chronic morphine treatment increases the expression of TNF-α, IL-1β, and IL-6 in activated glia in the DRG and spinal cord, which ultimately results in the decreased analgesic efficacy of morphine.…”

“…The prevailing evidence shows that acute and chronic morphine treatment increases the expression of TNF-α, IL-1β, and IL-6 in activated glia in the DRG and spinal cord, which ultimately results in the decreased analgesic efficacy of morphine. The development and maintenance of morphine tolerance are effectively prevented by inhibition of the synthesis of these cytokines or by their neutralization with specific antibodies in the spinal cord [15,[17][18][19][20] . NF-κB activation plays an important role in regulating the expression of TNF-α, IL-1β, IL-6, and other cytokines in immune cells [4] .…”

The effect of morphine upon DNA methylation in ten regions of the rat brain

“…There is also increasing evidence for a role of microglia in tolerance. Microglia are macrophages present within the central nervous system that produce pro-inflammatory cytokines such as interleukin 1 (IL-1), interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-) following their activation by morphine 4 . IL-1, IL-6 and TNF- have been shown to reduce morphine analgesia within five minutes of administration 4 , and blockade of IL-1 signalling prolongs morphine-induced analgesia 5 , thereby potentially implicating these three cytokines in morphine tolerance.…”