Glia: novel counter-regulators of opioid analgesia

Watkins, Linda R.; Hutchinson, Mark R.; Johnston, Ian; Maier, Steven F.

doi:10.1016/j.tins.2005.10.001

Cited by 302 publications

(249 citation statements)

References 64 publications

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“…Noticeably, studies by us (Song and Zhao, 2001) and others suggest that spinal glia may contribute to the development of morphine tolerance (Watkins et al, 2005).…”

Section: Introductionmentioning

confidence: 96%

Involvement of Spinal Microglial P2X7 Receptor in Generation of Tolerance to Morphine Analgesia in Rats

Zhou

Chen²,

Zhang³

2010

Journal of Neuroscience

102

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Morphine loses analgesic potency after repeated administration. The underlying mechanism is not fully understood. Glia are thought to be involved in morphine tolerance, and P2X 7 purinergic receptor (P2X 7 R) has been implicated in neuron-glia communication and chronic pain. The present study demonstrated that P2X 7 R immunoreactivity was colocalized with the microglial marker OX42, but not the astrocytic marker GFAP, in the spinal cord. The protein level of spinal P2X 7 R was upregulated after chronic exposure to morphine. Intrathecal administration of Brilliant Blue G (BBG), a selective P2X 7 R inhibitor, significantly attenuated the loss of morphine analgesic potency, P2X 7 R upregulation, and microglial activation. Furthermore, RNA interference targeting the spinal P2X 7 R exhibited a similar tolerance-attenuating effect. Once morphine analgesic tolerance is established, it was no longer affected by intrathecal BBG. Together, our results suggest that spinal P2X 7 R is involved in the induction but not maintenance of morphine tolerance.

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“…Noticeably, studies by us (Song and Zhao, 2001) and others suggest that spinal glia may contribute to the development of morphine tolerance (Watkins et al, 2005).…”

Section: Introductionmentioning

confidence: 96%

Involvement of Spinal Microglial P2X7 Receptor in Generation of Tolerance to Morphine Analgesia in Rats

Zhou

Chen²,

Zhang³

2010

Journal of Neuroscience

102

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“…These cytokines are upregulated in the spinal cord in chronic pain conditions. Functional inhibition of these cytokines can attenuate persistent pain and enhance opioid analgesia (Sweitzer et al, 2001;Watkins et al, 2001;Milligan et al, 2003;Watkins et al, 2005). However, the distinct roles of specific glial subtypes in pain sensitization were not assessed in these studies.…”

Section: Introductionmentioning

confidence: 99%

Possible role of spinal astrocytes in maintaining chronic pain sensitization: review of current evidence with focus on bFGF/JNK pathway

et al. 2006

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Although pain is regarded traditionally as neuronally mediated, recent progress shows an important role of spinal glial cells in persistent pain sensitization. Mounting evidence has implicated spinal microglia in the development of chronic pain (e.g. neuropathic pain after peripheral nerve injury). Less is known about the role of astrocytes in pain regulation. However, astrocytes have very close contact with synapses and maintain homeostasis in the extracellular environment. In this review, we provide evidence to support a role of spinal astrocytes in maintaining chronic pain. In particular, cJun N-terminal kinase (JNK) is activated persistently in spinal astrocytes in a neuropathic pain condition produced by spinal nerve ligation. This activation is required for the maintenance of neuropathic pain because spinal infusion of JNK inhibitors can reverse mechanical allodynia, a major symptom of neuropathic pain. Further study reveals that JNK is activated strongly in astrocytes by basic fibroblast growth factor (bFGF), an astroglial activator. Intrathecal infusion of bFGF also produces persistent mechanical allodynia. After peripheral nerve injury, bFGF might be produced by primary sensory neurons and spinal astrocytes because nerve injury produces robust bFGF upregulation in both cell types. Therefore, the bFGF/JNK pathway is an important signalling pathway in spinal astrocytes for chronic pain sensitization. Investigation of signaling mechanisms in spinal astrocytes will identify new molecular targets for the management of chronic pain.

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“…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.…”

Section: Introductionmentioning

confidence: 99%

“…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] .…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2014

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Nuclear factor kappa B (NF-κB) in the spinal cord is involved in pro-infl ammatory cytokine-mediated pain facilitation. However, the role of NF-κB activation in chronic morphine-induced analgesic tolerance and the underlying mechanisms remain unclear. In the present study, we found that the level of phosphorylated NF-κB p65 (p-p65) was increased in the dorsal horn of the lumbar 4-6 segments after intrathecal administration of morphine for 7 consecutive days, and the p-p65 was co-localized with neurons and astrocytes. The expression of TNF-α and IL-1β was also increased in the same area. In addition, pretreatment with pyrrolidinedithiocarbamate (PDTC) or SN50, inhibitors of NF-κB, prevented the development of morphine analgesic tolerance and alleviated morphine withdrawal-induced allodynia and hyperalgesia. The increase in TNF-α and IL-1β expression induced by chronic morphine exposure was also partially blocked by PDTC pretreatment. In another experiment, rats receiving PDTC or SN50 beginning on day 7 of morphine injection showed partial recovery of the anti-nociceptive effects of morphine and attenuation of the withdrawal-induced abnormal pain. Meanwhile, intrathecal pretreatment with lipopolysaccharide from Rhodobacter sphae roides, an antagonist of toll-like receptor 4 (TLR4), blocked the activation of NF-κB, and prevented the development of morphine tolerance and withdrawalinduced abnormal pain. These data indicated that TLR4-mediated NF-κB activation in the spinal cord is involved in the development and maintenance of morphine analgesic tolerance and withdrawalinduced pain hypersensitivity.

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Glia: novel counter-regulators of opioid analgesia

Cited by 302 publications

References 64 publications

Involvement of Spinal Microglial P2X7 Receptor in Generation of Tolerance to Morphine Analgesia in Rats

Involvement of Spinal Microglial P2X7 Receptor in Generation of Tolerance to Morphine Analgesia in Rats

Possible role of spinal astrocytes in maintaining chronic pain sensitization: review of current evidence with focus on bFGF/JNK pathway

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

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