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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