Corticotropin-Releasing Factor Mediates Pain-Induced Anxiety through the ERK1/2 Signaling Cascade in Locus Coeruleus Neurons

Abstract

Background:The corticotropin-releasing factor is a stress-related neuropeptide that modulates locus coeruleus activity. As locus coeruleus has been involved in pain and stress-related patologies, we tested whether the pain-induced anxiety is a result of the corticotropin-releasing factor released in the locus coeruleus.Methods:Complete Freund’s adjuvant-induced monoarthritis was used as inflammatory chronic pain model. α-Helical corticotropin-releasing factor receptor antagonist was microinjected into the contralateral locus coeruleus of 4-week-old monoarthritic animals. The nociceptive and anxiety-like behaviors, as well as phosphorylated extracellular signal-regulated kinases 1/2 and corticotropin-releasing factor receptors expression, were quantified in the paraventricular nucleus and locus coeruleus.Results:Monoarthritic rats manifested anxiety and increased phosphorylated extracellular signal-regulated kinases 1/2 levels in the locus coeruleus and paraventricular nucleus, although the expression of corticotropin-releasing factor receptors was unaltered. α-Helical corticotropin-releasing factor antagonist administration reversed both the anxiogenic-like behavior and the phosphorylated extracellular signal-regulated kinases 1/2 levels in the locus coeruleus.Conclusions:Pain-induced anxiety is mediated by corticotropin-releasing factor neurotransmission in the locus coeruleus through extracellular signal-regulated kinases 1/2 signaling cascade.

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

“…The development of anxio-depressive-like behaviors in chronic pain animal models has been reported in several studies [9,10,12,13,48]. Previous studies from our group have shown that anxiety-like behaviors in the CFA monoarthritis model are already present at 28 days [9,10,12].…”

“…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].…”

“…Thus, while DNIC studies indicate that these circuits might be compromised, a thorough evaluation of the descending noradrenergic system is still needed in joint inflammatory pain.The main spinal source of noradrenaline is the Locus coeruleus (LC), which presents a functional dichotomy, by modulating descending inhibition through its projections to the spinal cord, and by mediating emotional-related behaviors via its ascending targets [9,27]. Through these LC projections to brain regions implicated in the affective component of pain, such as the anterior cingulate cortex (ACC) and the amygdala, a noradrenergic impairment might be implicated on the onset of pain-induced emotional disorders [9,10,12]. Interestingly, Borges et al have shown that, in the CFA monoarthritis model, the expression of the phosphorylated extracellular signal-regulated kinases 1 and 2 (pERKs1/2), a neuronal activation marker, was increased in the LC, as well as in ACC and amygdala at 28 days of MA, and this was concomitant with the onset of emotional behavioral comorbidities [9,12].…”

“…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].…”

Neuroplasticity of Supraspinal Structures Associated with Pathological Pain

“…In an inflammatory chronic pain model (complete Freund's adjuvant‐induced monoarthritis model), the microinjection of CRF in the LC has been reported to cause nociceptive and anxiety‐like behaviors, while increasing the levels of phosphorylated extracellular signal‐regulated kinases 1/2 in both the LC and paraventricular nucleus, although the expression of CRF receptors remained unaltered. These findings suggest that, after inflammatory pain, pain‐induced anxiety is mediated by CRF neurotransmission in the LC through extracellular signal‐regulated kinases 1/2 signaling cascade (Borges et al, ) (Fig. ).…”