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J Neurosci. 2007 Aug 1;27(31):8226-37.
Control of chronic pain by the ubiquitin proteasome system in the spinal cord.
Ossipov MH, Bazov I, Gardell LR, Kowal J, Yakovleva T, Usynin I, Ekström TJ,
Porreca F, Bakalkin G.
Department of Pharmacology, University of Arizona Health Sciences Center, Tucson,
Arizona 85724, USA. [email protected]
Chronic pain is maintained in part by long-lasting neuroplastic changes in
synapses and several proteins critical for synaptic plasticity are degraded by
the ubiquitin-proteasome system (UPS). Here, we show that proteasome inhibitors
administered intrathecally or subcutaneously prevented the development and
reversed nerve injury-induced pain behavior. They also blocked pathological pain
induced by sustained administration of morphine or spinal injection of dynorphin
A, an endogenous mediator of chronic pain. Proteasome inhibitors blocked
mechanical allodynia and thermal hyperalgesia in all three pain models although
they did not modify responses to mechanical stimuli, but partially inhibited
responses to thermal stimuli in control rats. In the spinal cord, these compounds
abolished the enhanced capsaicin-evoked calcitonin gene-related peptide (CGRP)
release and dynorphin A upregulation, both elicited by nerve injury. Model
experiments demonstrated that the inhibitors may act directly on
dynorphin-producing cells, blocking dynorphin secretion. Thus, the effects of
proteasome inhibitors on chronic pain were apparently mediated through several
cellular mechanisms indispensable for chronic pain, including those of dynorphin
A release and postsynaptic actions, and of CGRP secretion. Levels of several UPS
proteins were reduced in animals with neuropathic pain, suggesting that UPS
downregulation, like effects of proteasome inhibitors, counteracts the
development of chronic pain. The inhibitors did not produce marked or disabling
motor disturbances at doses that were used to modify chronic pain. These results
suggest that the UPS is a critical intracellular regulator of pathological pain,
and that UPS-mediated protein degradation is required for maintenance of chronic
pain and nociceptive, but not non-nociceptive responses in normal animals.
Control of chronic pain by the ubiquitin proteasome system in the spinal cord.
Ossipov MH, Bazov I, Gardell LR, Kowal J, Yakovleva T, Usynin I, Ekström TJ,
Porreca F, Bakalkin G.
Department of Pharmacology, University of Arizona Health Sciences Center, Tucson,
Arizona 85724, USA. [email protected]
Chronic pain is maintained in part by long-lasting neuroplastic changes in
synapses and several proteins critical for synaptic plasticity are degraded by
the ubiquitin-proteasome system (UPS). Here, we show that proteasome inhibitors
administered intrathecally or subcutaneously prevented the development and
reversed nerve injury-induced pain behavior. They also blocked pathological pain
induced by sustained administration of morphine or spinal injection of dynorphin
A, an endogenous mediator of chronic pain. Proteasome inhibitors blocked
mechanical allodynia and thermal hyperalgesia in all three pain models although
they did not modify responses to mechanical stimuli, but partially inhibited
responses to thermal stimuli in control rats. In the spinal cord, these compounds
abolished the enhanced capsaicin-evoked calcitonin gene-related peptide (CGRP)
release and dynorphin A upregulation, both elicited by nerve injury. Model
experiments demonstrated that the inhibitors may act directly on
dynorphin-producing cells, blocking dynorphin secretion. Thus, the effects of
proteasome inhibitors on chronic pain were apparently mediated through several
cellular mechanisms indispensable for chronic pain, including those of dynorphin
A release and postsynaptic actions, and of CGRP secretion. Levels of several UPS
proteins were reduced in animals with neuropathic pain, suggesting that UPS
downregulation, like effects of proteasome inhibitors, counteracts the
development of chronic pain. The inhibitors did not produce marked or disabling
motor disturbances at doses that were used to modify chronic pain. These results
suggest that the UPS is a critical intracellular regulator of pathological pain,
and that UPS-mediated protein degradation is required for maintenance of chronic
pain and nociceptive, but not non-nociceptive responses in normal animals.
