Spinal protein kinase <scp>M</scp>ζ contributes to the maintenance of peripheral inflammation‐primed persistent nociceptive sensitization after plantar incision

An, Kai Nan; Zhen, Chao Jie; Liu, Z.-H.; Zhao, Qinghai; Liu, H.-P.; Xiao-long, Zhong; Huang, Wenqi

doi:10.1002/ejp.517

Cited by 15 publications

(18 citation statements)

References 42 publications

(75 reference statements)

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“…Other studies have indicated that p-PKMzeta is increased in the rostral ACC (rACC) and that rACC infusion of ZIP leads to a long-lasting reversal of chronic neuropathic pain in rats [ 42 ]. One study indicated that PKMzeta is responsible for the maintenance of peripheral inflammation-primed persistent postsurgical pain (PPSP) [ 43 ]. These results suggest that spinal PKMzeta plays an essential role in the maintenance of persistent pain by sustaining spinal nociceptive plasticity [ 41 ].…”

Section: Discussionmentioning

confidence: 99%

The Effect of Electroacupuncture on PKMzeta in the ACC in Regulating Anxiety-Like Behaviors in Rats Experiencing Chronic Inflammatory Pain

Fang

Chen

et al. 2017

Neural Plasticity

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Chronic inflammatory pain can induce emotional diseases. Electroacupuncture (EA) has effects on chronic pain and pain-related anxiety. Protein kinase Mzeta (PKMzeta) has been proposed to be essential for the maintenance of pain and may interact with GluR1 to maintain CNS plasticity in the anterior cingulate cortex (ACC). We hypothesized that the PKMzeta-GluR1 pathway in the ACC may be involved in anxiety-like behaviors of chronic inflammatory pain and that the mechanism of EA regulation of pain emotion may involve the PKMzeta pathway in the ACC. Our results showed that chronic inflammatory pain model decreased the paw withdrawal threshold (PWT) and increased anxiety-like behaviors. The protein expression of PKCzeta, p-PKCzeta (T560), PKMzeta, p-PKMzeta (T560), and GluR1 in the ACC of the model group were remarkably enhanced. EA increased PWT and alleviated anxiety-like behaviors. EA significantly inhibited the protein expression of p-PKMzeta (T560) in the ACC, and only a downward trend effect for other substances. Further, the microinjection of ZIP remarkably reversed PWT and anxiety-like behaviors. The present study provides direct evidence that the PKCzeta/PKMzeta-GluR1 pathway is related to pain and pain-induced anxiety-like behaviors. EA treatment both increases pain-related somatosensory behavior and decreases pain-induced anxiety-like behaviors by suppressing PKMzeta activity in the ACC.

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Section: Discussionmentioning

confidence: 99%

The Effect of Electroacupuncture on PKMzeta in the ACC in Regulating Anxiety-Like Behaviors in Rats Experiencing Chronic Inflammatory Pain

Fang

Chen

et al. 2017

Neural Plasticity

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“…There is growing evidence that PKMζ is involved in persistent nociceptive processing in the central nervous system. p-PKMζ was highly expressed in all categories of dorsal root ganglion (DRG) neurons in models of inflammatory pain [ 20 , 21 ]. PKMζ in the anterior cingulate cortex (ACC) contributed to pain maintenance induced by experimental tooth movement [ 22 ].…”

Section: Discussionmentioning

confidence: 99%

“…ZIP is a PKMζ inhibitor [ 27 ]. Previous results showed that incision sensitization was significantly inhibited after intrathecal ZIP injection following carrageenan-induced priming in a peripheral inflammation pain model [ 20 ]. After injection of ZIP, sensitization to both hindpaw injection of prostaglandin E2 and intrathecal administration of metabotropic glutamate receptor 1 and 5 agonist after the resolution of interleukin-6 (IL-6)-induced allodynia was completely abolished [ 7 ].…”

Section: Discussionmentioning

confidence: 99%

“…In IBS-like rats, visceral hypersensitivity decreased significantly 30–90 minutes after intrathecal ZIP injection, and then gradually increased and returned to baseline levels 3 hours later. The inhibitory effect of ZIP on the incision sensitization was long lasting; incision pain caused by carrageenan priming was alleviated for at least 16 days after ZIP injection [ 20 ]. ZIP completely abolished sensitization precipitated after injection of the hindpaw with prostaglandin E2 or dihydroxyphenylglycine in the interleukin-6-induced allodynia, and the effect lasted for several days, but it could not alter the IL-6-induced initial allodynia [ 7 ].…”

Section: Discussionmentioning

confidence: 99%

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Zeta Inhibitory Peptide as a Novel Therapy to Control Chronic Visceral Hypersensitivity in a Rat Model

Tang

Chen

et al. 2016

PLoS ONE

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BackgroundThe pathogenesis of multiple chronic visceral pain syndromes, such as irritable bowel syndrome (IBS), is not well known, and as a result current therapies are ineffective. The objective of this study was to investigate the effect of spinal protein kinase M zeta (PKMζ) on visceral pain sensitivity in rats with IBS to better understand the pathogenesis and investigate the effect of zeta inhibitory peptide (ZIP) as a therapy for chronic visceral pain.MethodsVisceral hypersensitivity rats were produced by neonatal maternal separation (NMS). Visceral pain sensitivity was assessed by electromyographic (EMG) responses of abdominal muscles to colorectal distention (CRD). Spinal PKMζ and phosphorylated PKMζ (p-PKMζ) were detected by western blot. Varying doses of ZIP were intrathecally administered to investigate the role of spinal PKMζ in chronic visceral hypersensitivity. The open field test was used to determine if ZIP therapy causes spontaneous motor activity side effects.ResultsGraded CRD pressure significantly increased EMG responses in NMS rats compared to control rats (p < 0.05). p-PKMζ expression increased in the thoracolumbar and lumbosacral spinal cord in the IBS-like rats with notable concomitant chronic visceral pain compared to control rats (p < 0.05). EMG data revealed that intrathecal ZIP injection (1, 5, and 10 μg) dose-dependently attenuated visceral pain hypersensitivity in IBS-like rats.ConclusionsPhosphorylated PKMζ may be involved in the spinal central sensitization of chronic visceral hypersensitivity in IBS, and administration of ZIP could effectively treat chronic visceral pain with good outcomes in rat models.

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“…Protein kinase M zeta (PKMζ), an autonomously active atypical PKC isoform, has been implicated in the maintenance of hippocampal LTP and memory, 8–11 as well as persistent pain states. 3,12–16 PKMζ is increased in the SCDH for a prolonged period following intraplantar (i.pl.) injection of formalin or capsaicin, as well as direct stimulation of SCDH nociceptive neurons by spinal injection of the glutamate agonist dihydroxyphenylglycine.…”

Section: Introductionmentioning

confidence: 99%

Sex differences in the contributions of spinal atypical PKCs and downstream targets to the maintenance of nociceptive sensitization

George¹,

Laferrière

Coderre

2019

Mol Pain

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Background: Chronic pain has been shown to depend on nociceptive sensitization in the spinal cord, and while multiple mechanisms involved in the initiation of plastic changes have been established, the molecular targets which maintain spinal nociceptive sensitization are still largely unknown. Building upon the established neurobiology underlying the maintenance of long-term potentiation in the hippocampus, this present study investigated the contributions of spinal atypical protein kinase C (PKC) isoforms PKCi/k and PKMf and their downstream targets (p62/GluA1 and NSF/GluA2 interactions, respectively) to the maintenance of spinal nociceptive sensitization in male and female rats. Results: Pharmacological inhibition of atypical PKCs by ZIP reversed established allodynia produced by repeated intramuscular acidic saline injections in male animals only, replicating previously demonstrated sex differences. Inhibition of both PKCi/k and downstream substrates p62/GluA1 resulted in male-specific reversals of intramuscular acidic saline-induced allodynia, while female animals continued to display allodynia. Inhibition of NSF/GluA2, the downstream target to PKMf, reversed allodynia induced by intramuscular acidic saline in both sexes. Neither PKCi/k, p62/GluA1 or NSF/GluA2 inhibition had any effect on formalin response for either sex. Conclusion: This study provides novel behavioural evidence for the male-specific role of PKCi/k and downstream target p62/GluA1, highlighting the potential influence of ongoing afferent input. The sexually divergent pathways underlying persistent pain are shown here to converge at the interaction between NSF and the GluA2 subunit of the AMPA receptor. Although this interaction is thought to be downstream of PKMf in males, these findings and previous work suggest that females may rely on a factor independent of atypical PKCs for the maintenance of spinal nociceptive sensitization.

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Spinal protein kinase Mζ contributes to the maintenance of peripheral inflammation‐primed persistent nociceptive sensitization after plantar incision

Cited by 15 publications

References 42 publications

The Effect of Electroacupuncture on PKMzeta in the ACC in Regulating Anxiety-Like Behaviors in Rats Experiencing Chronic Inflammatory Pain

The Effect of Electroacupuncture on PKMzeta in the ACC in Regulating Anxiety-Like Behaviors in Rats Experiencing Chronic Inflammatory Pain

Zeta Inhibitory Peptide as a Novel Therapy to Control Chronic Visceral Hypersensitivity in a Rat Model

Sex differences in the contributions of spinal atypical PKCs and downstream targets to the maintenance of nociceptive sensitization

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