Increases in the activated forms of ERK 1/2, p38 MAPK, and CREB are correlated with the expression of at-level mechanical allodynia following spinal cord injury

Crown, Eric D.; Ye, Zaiming; Johnson, Kathia M.; Xu, Guo Ying; McAdoo, David J.; Hulsebosch, Claire E.

doi:10.1016/j.expneurol.2006.01.003

Cited by 161 publications

(163 citation statements)

References 46 publications

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“…In our experiments, Western blot protein level detection of ERK, SAPK/JNK and p38MAPK was unmodified with respect to control in thalamus, PAG and cortex from chronic oxaliplatin rats. Phosphorylation level of these molecules decreased in thalamus for ERK and SAPK/JNK and in PAG and striatum for ERK whereas increased consistently in cortex and striatum for SAPK/JNK and mildly for ERK in spinal cord as previously shown in other kinds of neuropathic pain [4,6,18]. A dramatic increase in p38MAPK phosphorylated form could be observed in thalamus and PAG.…”

Section: Discussionsupporting

confidence: 54%

Supraspinal role of protein kinase C in oxaliplatin-induced neuropathy in rat

Norcini

Vivoli

Galeotti

et al. 2009

Pain

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a b s t r a c tOxaliplatin is a platinum-based chemotherapy drug characterized by the development of a painful peripheral neuropathy which is reproduced in rodent animal models with features observed in humans. Our focus was to explore the alterations of intracellular second messengers at supraspinal level in oxaliplatin-induced mechanical hyperalgesia. In our experiments, chronic administration of oxaliplatin to rats induced mechanical hyperalgesia which lasted for many days. When the hyperalgesic rats were submitted to paw pressure test in the presence of selective PKC inhibitor Calphostin C supraspinally administered, hyperalgesic effect could be reversed showing that PKC activity in supraspinal brain regions is needed. Concurrently, oxaliplatin chronic treatment induced a specific upregulation of c isoforms of PKC and increased phosphorylation of c/e PKC isoforms within thalamus and PAG. Phosphorylation was reversed when PKC activity was inhibited by Calphostin C. Distinct PKC-activated MAPK pathways, including p38MAPK, ERK1/2 and JNK, were investigated in chronic oxaliplatin rat. A dramatic phosphorylation increase, Calphostin C sensitive, could be observed in thalamus and PAG for p38MAPK. These data show that, in oxaliplatin-induced neuropathy, enhanced mechanical nociception is strictly correlated with increased phosphorylation of specific intracellular mediators in PAG and thalamus brain regions pointing to a role of these supraspinal centers in oxaliplatin-induced neuropathic pain mechanism. Ó

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Section: Discussionsupporting

confidence: 54%

Supraspinal role of protein kinase C in oxaliplatin-induced neuropathy in rat

Norcini

Vivoli

Galeotti

et al. 2009

Pain

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“…After SCI, chronic activation of microglia and astrocytes are found at the lesion site, caudal dorsal horn, and thalamus [21,[25][26][27][28][29][30]. Such changes have been implicated in the induction and maintenance of SCI pain.…”

Section: Introductionmentioning

confidence: 99%

Cell Cycle Activation Contributes to Increased Neuronal Activity in the Posterior Thalamic Nucleus and Associated Chronic Hyperesthesia after Rat Spinal Cord Contusion

Raver

Piao

et al. 2013

Neurotherapeutics

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Spinal cord injury (SCI) causes not only sensorimotor and cognitive deficits, but frequently also severe chronic pain that is difficult to treat (SCI pain). We previously showed that hyperesthesia, as well as spontaneous pain induced by electrolytic lesions in the rat spinothalamic tract, is associated with increased spontaneous and sensory-evoked activity in the posterior thalamic nucleus (PO). We have also demonstrated that rodent impact SCI increases cell cycle activation (CCA) in the injury region and that post-traumatic treatment with cyclin dependent kinase inhibitors reduces lesion volume and motor dysfunction. Here we examined whether CCA contributes to neuronal hyperexcitability of PO and hyperpathia after rat contusion SCI, as well as to microglial and astroglial activation (gliopathy) that has been implicated in delayed SCI pain. Trauma caused enhanced pain sensitivity, which developed weeks after injury and was correlated with increased PO neuronal activity. Increased CCA was found at the thoracic spinal lesion site, the lumbar dorsal horn, and the PO. Increased microglial activation and cysteine-cysteine chemokine ligand 21 expression was also observed in the PO after SCI. In vitro, neurons co-cultured with activated microglia showed up-regulation of cyclin D1 and cysteine-cysteine chemokine ligand 21 expression. In vivo, post-injury treatment with a selective cyclin dependent kinase inhibitor (CR8) significantly reduced cell cycle protein induction, microglial activation, and neuronal activity in the PO nucleus, as well as limiting chronic SCI-induced hyperpathia. These results suggest a mechanistic role for CCA in the development of SCI pain, through effects mediated in part by the PO nucleus. Moreover, cell cycle modulation may provide an effective therapeutic strategy to improve reduce both hyperpathia and motor dysfunction after SCI.

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“…46 Importantly, p38 MAPK modulates neuronal apoptosis following SCI, 47 and elevated levels of spinal p38 have been strongly implicated in the generation and maintenance of neuropathic pain in models of nerve and spinal cord injury. [48][49][50][51] Evidence suggests that these neurotoxic and hyperalgesic effects may result from p38-mediated glial activation and inflammation. 52 Treatment with p38 inhibitors prevents glial proliferation in the spinal cord and decreases the expression of neuropathic pain symptoms after injury.…”

Section: Figmentioning

confidence: 99%

Nor-Binaltorphimine Blocks the Adverse Effects of Morphine after Spinal Cord Injury

Aceves

Bancroft

Aceves

2017

Journal of Neurotrauma

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Opioids are frequently used for the treatment of pain following spinal cord injury (SCI). Unfortunately, we have shown that morphine administered in the acute phase of SCI results in significant, adverse secondary consequences including compromised locomotor and sensory recovery. Similarly, we showed that selective activation of the j-opioid receptor (KOR), even at a dose 32-fold lower than morphine, is sufficient to attenuate recovery of locomotor function. In the current study, we tested whether activation of the KOR is necessary to produce morphine's adverse effects using norBinaltorphimine (norBNI), a selective KOR antagonist. Rats received a moderate spinal contusion (T12) and 24 h later, baseline locomotor function and nociceptive reactivity were assessed. Rats were then administered norBNI (0, 0.02, 0.08, or 0.32 lmol) followed by morphine (0 or 0.32 lmol). Nociception was reassessed 30 min after drug treatment, and recovery was evaluated for 21 days. The effects of norBNI on morphine-induced attenuation of recovery were dose dependent. At higher doses, norBNI blocked the adverse effects of morphine on locomotor recovery, but analgesia was also significantly decreased. Conversely, at low doses, analgesia was maintained, but the adverse effects on recovery persisted. A moderate dose of norBNI, however, adequately protected against morphine's adverse effects without eliminating its analgesic efficacy. This suggests that activation of the KOR system plays a significant role in the morphineinduced attenuation of recovery. Our research suggests that morphine, and other opioid analgesics, may be contraindicated for the SCI population. Blocking KOR activity may be a viable strategy for improving the safety of clinical opioid use.

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Increases in the activated forms of ERK 1/2, p38 MAPK, and CREB are correlated with the expression of at-level mechanical allodynia following spinal cord injury

Cited by 161 publications

References 46 publications

Supraspinal role of protein kinase C in oxaliplatin-induced neuropathy in rat

Supraspinal role of protein kinase C in oxaliplatin-induced neuropathy in rat

Cell Cycle Activation Contributes to Increased Neuronal Activity in the Posterior Thalamic Nucleus and Associated Chronic Hyperesthesia after Rat Spinal Cord Contusion

Nor-Binaltorphimine Blocks the Adverse Effects of Morphine after Spinal Cord Injury

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