Extracellular signal‐regulated kinase activation in the chronic constriction injury model of neuropathic pain in anaesthetized rats

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

doi:10.1002/j.1532-2149.2012.00181.x

Cited by 15 publications

(12 citation statements)

References 63 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: 81%

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: 81%

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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“…On the brain, the labelling of pERK 1 2 was also studied at 42 days of monoarthritis, at the LC, the basolateral amygdala (BLa), and the ACC, to assess the levels of neuronal activation on regions implicated in the affective component of pain perception. These proteins are markers of neuronal activity and are particularly active on supraspinal areas when painful or pain-induced emotional behaviors are present [29].…”

Section: Immunohistochemistrymentioning

confidence: 99%

“…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].…”

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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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“…In the hypothalamic ARC and caudal DMN, a distinct pERK1/2 fiber labelling intensity was visually detected, thus separate quantification was performed as described (Borges et al, 2013) and values of pERK1/2 staining were expressed as optical density ratio using the free access software (ImageJ 1.49v). Hypothalamic ARC was divided in four levels according to bregma: level I (− 1.72 mm, − 1.80 mm and − 1.92 mm; 2 sections per animal, n = 23), level II (− 2.16 mm, − 2.28 mm and − 2.40 mm; 1–2 sections per animal, n = 24), level III (− 3.00 mm, − 3.12 mm and − 3.24 mm; 2 sections per animal, n = 24) and level IV (− 3.60 mm, − 3.72 mm and − 3.84 mm; 2 sections per animal, n = 23).…”

Section: Methodsmentioning

confidence: 99%

Neuroendocrine signaling modulates specific neural networks relevant to migraine

Martins-Oliveira

Akerman

Holland

et al. 2017

Neurobiology of Disease

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Migraine is a disabling brain disorder involving abnormal trigeminovascular activation and sensitization. Fasting or skipping meals is considered a migraine trigger and altered fasting glucose and insulin levels have been observed in migraineurs. Therefore peptides involved in appetite and glucose regulation including insulin, glucagon and leptin could potentially influence migraine neurobiology. We aimed to determine the effect of insulin (10 U·kg− 1), glucagon (100 μg·200 μl− 1) and leptin (0.3, 1 and 3 mg·kg− 1) signaling on trigeminovascular nociceptive processing at the level of the trigeminocervical-complex and hypothalamus. Male rats were anesthetized and prepared for craniovascular stimulation. In vivo electrophysiology was used to determine changes in trigeminocervical neuronal responses to dural electrical stimulation, and phosphorylated extracellular signal-regulated kinases 1 and 2 (pERK1/2) immunohistochemistry to determine trigeminocervical and hypothalamic neural activity; both in response to intravenous administration of insulin, glucagon, leptin or vehicle control in combination with blood glucose analysis. Blood glucose levels were significantly decreased by insulin (p < 0.001) and leptin (p < 0.01) whereas glucagon had the opposite effect (p < 0.001). Dural-evoked neuronal firing in the trigeminocervical-complex was significantly inhibited by insulin (p < 0.001), glucagon (p < 0.05) and leptin (p < 0.01). Trigeminocervical-complex pERK1/2 cell expression was significantly decreased by insulin and leptin (both p < 0.001), and increased by glucagon (p < 0.001), when compared to vehicle control. However, only leptin affected pERK1/2 expression in the hypothalamus, significantly decreasing pERK1/2 immunoreactive cell expression in the arcuate nucleus (p < 0.05). These findings demonstrate that insulin, glucagon and leptin can alter the transmission of trigeminal nociceptive inputs. A potential neurobiological link between migraine and impaired metabolic homeostasis may occur through disturbed glucose regulation and a transient hypothalamic dysfunction.

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Extracellular signal‐regulated kinase activation in the chronic constriction injury model of neuropathic pain in anaesthetized rats

Abstract: ERK1/2 are differentially activated in the spinal cord and in selected brainstem nuclei implicated in nociception, in response to an acute noxious stimulus and/or to a neuropathic pain condition.

Cited by 15 publications

References 63 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

Neuroendocrine signaling modulates specific neural networks relevant to migraine

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