Activation of Extracellular Signal-Regulated Kinases (ERK 1/2) in the Locus Coeruleus Contributes to Pain-Related Anxiety in Arthritic Male Rats

Abstract

Background:There is increasing evidence suggesting that the Locus Coeruleus plays a role in pain-related anxiety. Indeed, we previously found that prolonged arthritis produces anxiety-like behavior in rats, along with enhanced expression of phosphorylated extracellular signal-regulated kinase 1/2 (a marker of plasticity) in the Locus Coeruleus. However, it is unknown how this effect correlates with the electrophysiological activity of Locus Coeruleus neurons or pain-related anxiety.Methods:Using the complete Freund’s adjuvant model of monoarthritis in male Sprague-Dawley rats, we studied the behavioral attributes of pain and anxiety as well as Locus Coeruleus electrophysiology in vivo 1 (MA1W) and 4 weeks (MA4W) after disease induction.Results:The manifestation of anxiety in MA4W was accompanied by dampened tonic Locus Coeruleus activity, which was coupled to an exacerbated evoked Locus Coeruleus response to noxious stimulation of the inflamed and healthy paw. When a mitogen-activating extracellular kinase inhibitor was administered to the contralateral Locus Coeruleus of MA4W, the phosphorylated extracellular signal-regulated kinase 1/2 levels in the Locus Coeruleus were restored and the exaggerated evoked response was blocked, reversing the anxiogenic-like behavior while pain hypersensitivity remained unaltered.Conclusion:As phosphorylated extracellular signal-regulated kinase 1/2 blockade in the Locus Coeruleus relieved anxiety and counteracted altered LC function, we propose that phosphorylated extracellular signal-regulated kinase 1/2 activation in the Locus Coeruleus plays a crucial role in pain-related anxiety.

Tannins from Terminalia chebula fruits attenuates GABA antagonist-induced anxiety-like behaviour via modulation of neurotransmitters

“…In the anxiogenic conditions, a large number of protein kinase cascades will be activated and responsible for various functions, including neurotransmitter release and receptor binding. Among the cascade of events, activation of ERK ½ (extracellular signal‐regulated kinases) is one of the important causes of hyperactivation of neurons in anxiety . In the present study, supplementation of TCHE had up‐regulated ERK ½ and p‐ERK ½ in a dose‐dependent manner when compared to PTX group.…”

“…Among the cascade of events, activation of ERK ½ (extracellular signal-regulated kinases) is one of the important causes of hyperactivation of neurons in anxiety. [48] In the present study, supplementation of TCHE had up-regulated ERK ½ and p-ERK ½ in a dose-dependent manner when compared to PTX group. Tannins of TCHE may exert a significant anxiolytic effects by binding to GABA site and enhancing monoaminergic neurotransmission.…”

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

“…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.…”

“…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].…”

“…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]. However, in chronic joint inflammatory pain conditions, it is unclear if these changes in supraspinal activity and affective behaviors correlate with alterations at the spinal level in the descending noradrenergic system.In the present study, to understand how these spinal, descending modulation and pain-related affective circuits are affected by a chronic joint inflammatory pain condition, we have used the monoarthritis rat model to examine different components essential for the pain experience, namely the spinal nociceptive system, the descending pain modulatory system, and the affective component, with a special focus on the noradrenergic system.…”