Role of PKC‐α,γ isoforms in regulation of c‐Fos and TH expression after naloxone‐induced morphine withdrawal in the hypothalamic PVN and medulla oblongata catecholaminergic cell groups

Benavides, Marta; Laorden, M. Luisa; Marín, María Teresa Martínez; Milanés, M. Victoria

doi:10.1111/j.1471-4159.2005.03445.x

Cited by 15 publications

(20 citation statements)

References 54 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Previous reports from our laboratory indicate that inhibition of PKC significantly blocked the corticosterone secretion during morphine withdrawal (50). These findings are consistent with the observation that PKC is up-regulated in the PVN during morphine dependence and may suggest that PKC activity is necessary for the increased HPA axis activity during morphine withdrawal (41).…”

Section: Discussionsupporting

confidence: 87%

“…Recent findings from our group have also shown the involvement of an up-regulated cAMP-dependent protein kinase A in activating TH levels and c-Fos expression in the NTS during morphine withdrawal (40). In addition, we have also shown that activated PKC may be critical for the activation of the catecholaminergic brain stem cell groups in response to opioid withdrawal (41). In the present study, it should be noted that TH protein expression was increased in NTS in morphine dependent rats, suggesting that the effect of morphine is mediated through both the activation (via phosphorylation) of TH and the up-regulation of its expression, which is in agreement with previous results from this laboratory (14).…”

Section: Discussionmentioning

confidence: 74%

See 1 more Smart Citation

Regulation of Serine (Ser)-31 and Ser40 Tyrosine Hydroxylase Phosphorylation during Morphine Withdrawal in the Hypothalamic Paraventricular Nucleus and Nucleus Tractus Solitarius-A2 Cell Group: Role of ERK1/2

2007

Self Cite

View full text Add to dashboard Cite

Our previous studies have shown that naloxone-induced morphine withdrawal increases the hypothalamic-pituitary-adrenocortical (HPA) axis activity, which is dependent on a hyperactivity of noradrenergic pathways [nucleus tractus solitarius (NTS) A(2)] innervating the hypothalamic paraventricular nucleus (PVN). Short-term regulation of catecholamine biosynthesis occurs through phosphorylation of tyrosine hydroxylase (TH), which enhances enzymatic activity. In the present study, the effect of morphine withdrawal on site-specific TH phosphorylation in the PVN and NTS-A(2) was determined by quantitative blot immunolabeling and immunohistochemistry using phosphorylation state-specific antibodies. We show that naloxone-induced morphine withdrawal phosphorylates TH at Serine (Ser)-31 but not Ser40 in PVN and NTS-A(2), which is associated with both an increase in total TH immunoreactivity in NTS-A(2) and an enhanced TH activity in the PVN. In addition, we demonstrated that TH neurons phosphorylated at Ser31 coexpress c-Fos in NTS-A(2). We then tested whether pharmacological inhibition of ERK activation by ERK kinase contributes to morphine withdrawal-induced phosphorylation of TH at Ser31. We show that the ability of morphine withdrawal to stimulate phosphorylation at this seryl residue is reduced by SL327, an inhibitor of ERK(1/2) activation. These results suggest that morphine withdrawal increases noradrenaline turnover in the PVN, at least in part, via ERK(1/2)-dependent phosphorylation of TH at Ser31.

show abstract

Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 74%

Regulation of Serine (Ser)-31 and Ser40 Tyrosine Hydroxylase Phosphorylation during Morphine Withdrawal in the Hypothalamic Paraventricular Nucleus and Nucleus Tractus Solitarius-A2 Cell Group: Role of ERK1/2

2007

Self Cite

View full text Add to dashboard Cite

show abstract

“…2008) whereas chronic perfusion with calphostin C reported clear inhibition of morphine withdrawal‐induced neuroendocrine changes in rats (Cerezo et al. 2002; Benavides et al. 2005).…”

Section: Methodsmentioning

confidence: 99%

Morphine withdrawal regulates phosphorylation of cAMP response element binding protein (CREB) through PKC in the nucleus tractus solitarius‐A₂ catecholaminergic neurons

Martín

Laorden

Milanés

2009

Journal of Neurochemistry

Self Cite

View full text Add to dashboard Cite

The transcription factor cAMP response element binding protein (CREB) has been implicated in the actions of drugs of abuse in several brain areas. However, little is known about CREB regulation in the nucleus tractus solitarius (NTS)‐A2 catecholaminergic cell group, one of the key regions of the brain stress system. Morphine withdrawal modulates gene expression in the NTS through various second‐messenger signal transduction systems including activation of extracellular signal‐regulated kinases 1/2 (ERK1/2) and protein kinase C (PKC). In the current study we used immunoblotting and immunohistochemistry to investigate changes in CREB phosphorylation in the NTS and kinases that may mediate the morphine withdrawal‐triggered activation of CREB and hypothalamo‐pituitary‐adrenocortical (HPA) axis (another stress system circuit) response after naloxone‐induced morphine withdrawal. We found an increased phosphorylation of CREB (pCREB) selectively within tyrosine hydroxylase (TH) immunoreactive neurons in the NTS from morphine‐withdrawn rats, which parallel elevated corticosterone levels. We also measured expression levels of TH and phosphorylated ERK1/2 (pERK1/2), and found that both are up‐regulated following morphine withdrawal. SL327, an inhibitor of ERK activation, at doses which reduced the hyperactive pERK1/2 levels, did not attenuated the rise in pCREB and TH immunoreactivity or plasma corticosterone secretion during morphine withdrawal, indicating that ERK kinase/ERK pathway was not directly needed for either activation of CREB and TH expression in the NTS or HPA axis hyperactivity. In contrast, PKC inhibitor calphostin C reduced the withdrawal‐triggered rise in pCREB, pERK1/2, TH expression and corticosterone secretion. The results indicate that PKC mediates both CREB activation and HPA response by morphine withdrawal and might suggest that CREB activation in the NTS is related to TH expression associated with morphine withdrawal.

show abstract

“…We observed a partial colocalization (laminae I-II), suggesting that pERK1/2 could contribute to c-Fos expression in our in vivo model. However, a similar number of c-Fos-positive neurons did not coexpress pERK1/2, indicating that alternative pathways such as protein kinase A, protein kinase C, and p38 kinase could also regulate c-Fos expression (Benavides et al, 2005;Svensson et al, 2005;Gonzá lez-Cuello et al, 2007). Regarding the association between ERK1/2 and c-Fos, some in vivo studies show that in the spinal cord, ERK1/2 is required for c-Fos expression after noxious stimulation (Cruz et al, 2007;Zhang et al, 2009), whereas others illustrate c-Fos expression in the absence of ERK1/2 activation in different animal models (Ji and Rupp, 1997;Kominato et al, 2003).…”

Section: Downloaded Frommentioning

confidence: 99%

Increased Spinal Dynorphin Levels and Phospho-Extracellular Signal-Regulated Kinases 1 and 2 and c-Fos Immunoreactivity after Surgery under Remifentanil Anesthesia in Mice

Campillo

González-Cuello²,

Cabañero³

et al. 2009

Mol Pharmacol

Self Cite

View full text Add to dashboard Cite

In humans, remifentanil anesthesia enhances nociceptive sensitization in the postoperative period. We hypothesized that activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and the expression of c-Fos, prodynorphin (mRNA), and dynorphin in the spinal cord could participate in the molecular mechanisms underlying postoperative opioid-induced sensitization. In a mouse model of incisional pain, we evaluated thermal (Hargreaves test) and mechanical (von Frey) hyperalgesia during the first 21 postoperative days. Moreover, prodynorphin (mRNA, real-time polymerase chain reaction), dynorphin (enzymatic immunoassay), c-Fos expression, and ERK1/2 phosphorylation (both by immunohistochemistry) in the lumbar spinal cord were assessed. Surgery performed under remifentanil anesthesia induced a maximal decrease in nociceptive thresholds between 4 h and 2 days postoperatively (p Ͻ 0.001) that lasted 10 to 14 days compared with noninjured animals. In the same experimental conditions, a significant increase in prodynorphin mRNA expression (at 2 and 4 days) followed by a sustained increase of dynorphin (days 2 to 10) in the spinal cord was observed. We also identified an early expression of c-Fos immunoreactivity in the superficial laminae of the dorsal horn of the spinal cord (peak at 4 h; p Ͻ 0.001), together with a partial activation of ERK1/2 (4 h; p Ͻ 0.001). These findings suggest that activated ERK1/2 could induce c-Fos expression and trigger the transcription of prodynorphin in the spinal cord. This in turn would result in long-lasting increased levels of dynorphin that, in our model, could participate in the persistence of pain but not in the manifestation of first pain.In humans, exposure to -opioid receptor agonists during anesthesia induces delayed hyperalgesia, increasing pain and analgesic requirements in the postoperative period (Angst and Clark, 2006). The pronociceptive effects of opioids have also been reported in human volunteers and in animal models (Li et al., 2001;Angst et al., 2003). In a mouse model of postoperative pain, we have shown that postincisional pain is enhanced when the ultra-short-acting -opioid receptor agonist remifentanil is administered during anesthesia (Célé rier et al., 2006;Cabañ ero et al., 2009b). Remifentanil is commonly used in clinical practice to provide analgesia during surgery, although it has been associated with hyperalgesia in the immediate postoperative period (Angst and Clark, 2006;Joly et al., 2005).The mechanisms and signal transduction pathways that mediate pain sensitization after opioid administration are not well known. Multiple central and peripheral pathways and mechanisms have been implicated, including C-fiber sensitization, protein kinase C, the nitric oxide system, N-methyl-D-aspartate (NMDA) receptors, mitogen-activated protein kinases (MAPKs) and spinal dynorphin, among others (Angst and Clark, 2006). It has also been shown that down-regulation of ␦-opioid receptor mRNA in the dorsal root ganglia contributes to remifentanil and surgery-i...

show abstract

Role of PKC‐α,γ isoforms in regulation of c‐Fos and TH expression after naloxone‐induced morphine withdrawal in the hypothalamic PVN and medulla oblongata catecholaminergic cell groups

Cited by 15 publications

References 54 publications

Regulation of Serine (Ser)-31 and Ser40 Tyrosine Hydroxylase Phosphorylation during Morphine Withdrawal in the Hypothalamic Paraventricular Nucleus and Nucleus Tractus Solitarius-A2 Cell Group: Role of ERK1/2

Regulation of Serine (Ser)-31 and Ser40 Tyrosine Hydroxylase Phosphorylation during Morphine Withdrawal in the Hypothalamic Paraventricular Nucleus and Nucleus Tractus Solitarius-A2 Cell Group: Role of ERK1/2

Morphine withdrawal regulates phosphorylation of cAMP response element binding protein (CREB) through PKC in the nucleus tractus solitarius‐A₂ catecholaminergic neurons

Increased Spinal Dynorphin Levels and Phospho-Extracellular Signal-Regulated Kinases 1 and 2 and c-Fos Immunoreactivity after Surgery under Remifentanil Anesthesia in Mice

Contact Info

Product

Resources

About

Role of PKC‐α,γ isoforms in regulation of c‐Fos and TH expression after naloxone‐induced morphine withdrawal in the hypothalamic PVN and medulla oblongata catecholaminergic cell groups

Cited by 15 publications

References 54 publications

Regulation of Serine (Ser)-31 and Ser40 Tyrosine Hydroxylase Phosphorylation during Morphine Withdrawal in the Hypothalamic Paraventricular Nucleus and Nucleus Tractus Solitarius-A2 Cell Group: Role of ERK1/2

Regulation of Serine (Ser)-31 and Ser40 Tyrosine Hydroxylase Phosphorylation during Morphine Withdrawal in the Hypothalamic Paraventricular Nucleus and Nucleus Tractus Solitarius-A2 Cell Group: Role of ERK1/2

Morphine withdrawal regulates phosphorylation of cAMP response element binding protein (CREB) through PKC in the nucleus tractus solitarius‐A2 catecholaminergic neurons

Increased Spinal Dynorphin Levels and Phospho-Extracellular Signal-Regulated Kinases 1 and 2 and c-Fos Immunoreactivity after Surgery under Remifentanil Anesthesia in Mice

Contact Info

Product

Resources

About

Morphine withdrawal regulates phosphorylation of cAMP response element binding protein (CREB) through PKC in the nucleus tractus solitarius‐A₂ catecholaminergic neurons