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In normal circumstances, pain sensation signals tissue injury that could compromise the organism's survival and its welfare. In this sense, pain experience is composed of a sensory dimension, which includes the perception of location, quality, and intensity of a noxious stimulus, as well as an emotional dimension that processes the unpleasantness of the noxious stimulus. However, maintained painful states (chronic pain) may derive in pathological conditions with emotional, affective, and social implications. Indeed, many epidemiological studies have showed a deep relationship between the intensity of unpleasantness sensation and secondary emotions associated such as suffering and stress. This situation after a period of time may derive in psychiatric disorders, being the most common depression and anxiety. Once this happens, it enters in a vicious circle in which the worsening of affective sphere aggravates the pain perception and vice versa, worsening the patient’s prognosis.

The knowledge of the underlying bases of these processes would help to develop new approaches to improve the diagnosis and treatment of chronic pain patients. In chronic pain, action potentials fire at a higher rate in nociceptors, which carry pain information to several brain areas. Thus, mood disorders may be the result of functionally impairment of neural substrates that affect pain, emotion, reward and/or motivation processing. To study the substrates that might impinge on these different circuits, we explored the role of the noradrenergic nucleus locus coeruleus (LC) to test the hypothesis that altered LC function may promote depressive and anxiogenic behavior in chronic pain. The LC is a relevant structure in both ascending and descending pain transmission. As the primary source of noradrenaline to the prefrontal cortex, the LC is regarded as part of the central “stress circuitry” involved in the pathophysiology of depression and anxiety disorders.

With this aim, we have investigated the function of LC nucleus in a peripheral model of neuropathic pain (the chronic constriction injury (CCI)). This is an animal model that mimics most of the symptoms seen in clinical setting such as allodynia (pain due to a stimulus which does not normally provoke pain) and hyperalgesia (increased sensitivity to pain). At early stages of neuropathy development, the sensory dimension of pain was measured by testing the pain threshold, which decreased consistently from day 2 after inducing pain. We also explored the aversiveness of painful experiences with the place escape/avoidance test. This test permits the aversive nature of a noxious stimulus to be assessed on the basis of avoiding a preferred location (non anxiogenic area) where the stimulus is delivered. Accordingly, the pain group at early stage (1 week after injury) showed a higher preference for the anxiogenic area than the control group, showing that aversion to a painful experience increase in neuropathic rats. Strikingly, this preference was completely abolished in long-term neuropathic rats (4 weeks after injury). Furthermore, long-term neuropathic rats spent a substantially longer time in the non anxiogenic area area compared with control or short-term neuropathic rats, despite both pain groups having a similar sensorial pain threshold. This shows that anxiety is more significant than experiencing emotional pain in long-term neuropathic rats. Further studies showed that long-term neuropathic pain resulted in an inability to cope with stressful situations, provoking depressive and anxiogenic-like behaviors. This suggests that long-term chronic pain leads to emotional disorders that are more relevant than the intrinsic suffering caused by a painful stimulation.

Regarding LC neurons, its tonic (spontaneous) function was not modified in spite of pain hypersensitivity was already present at early stages (1 week after injury). Indeed, no changes were observed in the neuronal tonic activity, alpha2-adrenoreceptors sensitivity and expression, G protein and RGS levels, and noradrenaline release in LC and prefrontal cortex. Although the tonic activity of LC was not modified in this early staged of CCI, phasic LC discharge upon nociceptive mechanical and electrical stimulations in the ipsilateral paw was alredy altered. However, long-term neuropathic pain temporally coincided with marked tonic (spontaneous) modifications of noradrenergic LC neurons. Indeed, we found an altered expression of tyrosine hydroxylase, noradrenaline transporter and alpha2-adrenoreceptors proteins that influenced on neuronal firing activity and noradrenaline release. Interestingly, similar changes in tyrosine hydroxylase, noradrenaline transporter and alpha2-adrenoreceptors levels in the LC have been described in animal models of depression and in post-mortem brain tissue of depressed individuals. In addition, nerve-injured rats showed an exacerbated phasic response upon nociceptive stimulation one month after the surgery. On the other hand, the treatment (one week) with desipramine (noradrenaline reuptake inhibitor) or duloxetine (serotonin and noradrenaline reuptake inhibitor) at the same time of CCI surgery prevented the alterations on phasic LC activity in parallel with their behavioural analgesic and antidepressant effects.

When painful stimulus reaches the LC, noradrenergic neurons are activated, promoting noradrenaline release in both the LC and terminal areas like the spinal cord, contributing to the normal control of pain perception. However, as a consequence of spontaneous or evoked pain in chronic pain conditions, the LC might constantly receive nociceptive inputs, increasing noradrenaline requirements as well as leading to secondary homeostatic compensations that may cause the mood disorders in CCI animals. Therefore, the present study presents biological data to support the use of these noradrenaline reuptake inhibitors (antidepressants) to treat pain and its long-term consequences (mood disorders).