ERK1/2: Function, signaling and implication in pain and pain-related anxio-depressive disorders

Borges, Gisela; Berrocoso, Esther; Micó, J.A.; Neto, Francisco Piorino

doi:10.1016/j.pnpbp.2015.02.010

Cited by 31 publications

(20 citation statements)

References 170 publications

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“…Furthermore, the pERK1/2-positive cells detected in the dorsal horn superficial laminae exhibited a fusiform body with few extensions, suggesting a neuronal phenotype. This was confirmed by pERK1/2 labelling, which predominantly surrounded the nuclei of neurons and did not co-localize with microglia or astrocytes cellular markers, supporting the idea that pERK1/2 cascade is involved in chronic pain modulation in neuronal pathways (Borges, Berrocoso, Mico, & Neto, 2015;Borges, Berrocoso, Ortega-Alvaro, Mico, & Neto, 2013). In our study, the animals' affected hindpaw was repeatedly stimulated at specific days after the SNI surgery and SNI animals were tested 2 hr before sacrifice.…”

Section: Discussionsupporting

confidence: 82%

Amylin, a peptide expressed by nociceptors, modulates chronic neuropathic pain

Almeida

Castro-Lopes

Neto

et al. 2019

European Journal of Pain

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Background Amylin is a calcitonin gene‐related peptide family member expressed by nociceptors. Amylin's expression is down‐regulated following nerve damage, and studies suggested it affects nociception. We aimed at clarifying amylin's effects on chronic neuropathic pain and investigating its site of action. Methods Chronic neuropathic pain was induced in rats by spared nerve injury (SNI) surgery. Mechanical allodynia/hyperalgesia and cold allodynia/hyperalgesia were assessed by the von Frey, pinprick, acetone and cold plate behavioural tests, respectively. Amylin, amylin‐receptor antagonist (AC187) or vehicle solutions were delivered chronically, by a subcutaneous (SC) mini‐osmotic pump, or acutely, by SC or intrathecal (IT) injections. Cellular and fibre markers were used to detect spinal cord alterations in SNI rats after chronic amylin administration. Results Continuous subcutaneous amylin administration aggravated cold allodynia in SNI animals, possibly via amylin‐receptors (AmyR) in supraspinal areas. Acute intrathecal administration of amylin attenuated mechanical hyperalgesia, whereas AC187 reduced mechanical allodynia, suggesting distinct roles of endogenous amylin and of pharmacological amylin doses when targeting spinal cord amylin receptors. Chronic amylin administration promoted c‐Fos activation only in the dorsal horn neurons of SHAM animals, suggesting a distinctive role of amylin in the activation of the spinal neuronal circuitry under neuropathic and physiological conditions. ERK1/2 phosphorylation increased in the dorsal horn neurons of SNI rats chronically treated with amylin. This ERK1/2 cascade activation may be related to amylin's effect on the aggravation of cold allodynia in SNI rats. Conclusions Amylin's nociceptive effects seem to depend on the treatment duration and route of administration by acting at different levels of the nervous system. Significance Amylin modulated neuropathic pain by acting at different levels of the nervous system. Whereas supraspinal areas may be involved in amylin's induced pronociception, modulation of spinal cord amylin receptors by endogenous or pharmacological amylin doses triggers both pro‐ and antinociceptive effects.

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Section: Discussionsupporting

confidence: 82%

Amylin, a peptide expressed by nociceptors, modulates chronic neuropathic pain

Almeida

Castro-Lopes

Neto

et al. 2019

European Journal of Pain

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“…Interestingly, the DNIC attenuation at 42 days after the indution of monoarthritis with CFA was also concomitant with changes in the neuronal activity of several cortical and subcortical brain areas, which were evaluated by the activation of ERK1/2. The ERK1/2 are enzymes that have been used for a few years as markers of neuronal activity associated with painful conditions and, with the development of pain-induced emotional comorbidities, such as anxiety-and depressive-like behaviors [12,28]. At 42 days, we found that the activation of ERK1/2 was highly increased in the LC of monoarthritic rats, indicating a rise in neuronal activity [28].…”

Section: Discussionmentioning

confidence: 70%

“…Finally, to assess the integrity of the affective component in this model, we have evaluated pain-induced anxiety and depressive-like behaviors. We have further assessed the neuronal activity in the LC and in supraspinal affective-related areas associated with the pain's emotional component by quantifying the immunolabeling of pERKs1/2, which is a marker of neuronal activity associated with these pain-induced anxiety and depressive-like behaviors in chronic joint pain models [9,10,28,29].…”

mentioning

confidence: 99%

Attenuation of the Diffuse Noxious Inhibitory Controls in Chronic Joint Inflammatory Pain Is Accompanied by Anxiodepressive-Like Behaviors and Impairment of the Descending Noradrenergic Modulation

Pereira-Silva

Costa‐Pereira

Alonso

et al. 2020

IJMS

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The noradrenergic system is paramount for controlling pain and emotions. We aimed at understanding the descending noradrenergic modulatory mechanisms in joint inflammatory pain and its correlation with the diffuse noxious inhibitory controls (DNICs) and with the onset of anxiodepressive behaviours. In the complete Freund's adjuvant rat model of Monoarthritis, nociceptive behaviors, DNICs, and anxiodepressive-like behaviors were evaluated. Spinal alpha2-adrenergic receptors (a2-AR), dopamine beta-hydroxylase (DBH), and noradrenaline were quantified concomitantly with a2-AR pharmacologic studies. The phosphorylated extracellular signal-regulated kinases 1 and 2 (pERK1/2) were quantified in the Locus coeruleus (LC), amygdala, and anterior cingulate cortex (ACC). DNIC was attenuated at 42 days of monoarthritis while present on days 7 and 28. On day 42, in contrast to day 28, noradrenaline was reduced and DBH labelling was increased. Moreover, spinal a2-AR were potentiated and no changes in a2-AR levels were observed. Additionally, at 42 days, the activation of ERKs1/2 was increased in the LC, ACC, and basolateral amygdala. This was accompanied by anxiety-and depressive-like behaviors, while at 28 days, only anxiety-like behaviors were observed. The data suggest DNIC is attenuated in prolonged chronic joint inflammatory pain, and this is accompanied by impairment of the descending noradrenergic modulation and anxiodepressive-like behaviors. IntroductionJoint inflammatory pain is a highly prevalent condition [1,2], and the available treatments are often inefficient and have various adverse side-effects [3]. The pathophysiological mechanisms underlying pain, in these chronic conditions, are still not completely understood [4][5][6][7][8].Chronic pain involves many different complex processes in key spinal and supraspinal areas, which may suffer significant changes in an attempt to adapt to the ongoing noxious stimuli [4,5,7]. Indeed, the control of pain implies several molecular changes at the spinal cord, in the descending modulation of pain, and in supraspinal areas involved in the emotional component of pain processing [4,5,7,[9][10][11]. The latter may be influenced and altered by the noxious stimuli and also may be responsible for changes in the way these pathologic stimuli are processed [9,12,13]. Despite this knowledge, much is still unclear about how and when these changes in pain processing occur during the progression of a chronic joint inflammatory painful condition. Indeed, the balance between facilitatory and inhibitory input is compromised in chronic pain [4,14]. Through the release of noradrenaline at the spinal cord, the descending noradrenergic system is implicated in the spinal inhibition of noxious input, modulating the transmission of nociceptive information [4,15]. This descending noradrenergic input is impaired in neuropathic pain conditions [16][17][18]. Although in joint inflammatory pain this is rather unexplored, the few studies performed suggest the presence of changes in this modulatory syste...

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“…The descending pathways regulate nociceptive signaling in the spinal cord. It has been reported that chronic stress activates or suppress neuronal activity in the LC, and neuropathic pain suppress neuronal activity in the LC, which is associated with the development of anxiety-like behaviors in mice (Borges et al, 2015). Selective depletion of noradrenaline in the LC causes anxiety- and depression-like behaviors (Itoi et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Astrocyte Activation in Locus Coeruleus Is Involved in Neuropathic Pain Exacerbation Mediated by Maternal Separation and Social Isolation Stress

et al. 2017

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Our previous studies demonstrated that emotional dysfunction associated with early life stress exacerbated nerve injury-induced mechanical allodynia. Sex differences were observed in several anxiety tests, but not in mechanical allodynia. To elucidate the mechanism underlying these findings, we have now investigated the involvement of astrocytes in emotional dysfunction and enhancement of nerve injury-induced mechanical allodynia in mice subjected to maternal separation combined with social isolation (MSSI) as an early life stress. We measured expression of glial fibrillary acidic protein (GFAP), an astrocyte maker, in each brain area by immunohistochemistry. GFAP expression in the locus coeruleus (LC) of female, but not of male mice, significantly increased after MSSI, corresponding to the behavioral changes at 7 and 12 weeks of age. Lipopolysaccharide (LPS)-treated astrocyte-derived supernatant was administered to local brain regions, including LC. Intra-LC injection of conditioned medium from cultured astrocytes treated with LPS increased GFAP expression, anxiety-like behavior and mechanical allodynia in both male and female mice. Furthermore, increases in anxiety-like behavior correlated with increased mechanical allodynia. These findings demonstrate that emotional dysfunction and enhanced nerve injury-induced mechanical allodynia after exposure to MSSI are mediated, at least in part, by astrocyte activation in the LC. Male but not female mice may show resistance to MSSI stress during growth.

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ERK1/2: Function, signaling and implication in pain and pain-related anxio-depressive disorders

Cited by 31 publications

References 170 publications

Amylin, a peptide expressed by nociceptors, modulates chronic neuropathic pain

Amylin, a peptide expressed by nociceptors, modulates chronic neuropathic pain

Attenuation of the Diffuse Noxious Inhibitory Controls in Chronic Joint Inflammatory Pain Is Accompanied by Anxiodepressive-Like Behaviors and Impairment of the Descending Noradrenergic Modulation

Astrocyte Activation in Locus Coeruleus Is Involved in Neuropathic Pain Exacerbation Mediated by Maternal Separation and Social Isolation Stress

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