The locus coeruleus (LC)-noradrenergic system is the main source of noradrenaline in the central nervous system and is involved intensively in modulating pain and stress-related disorders (e.g., major depressive disorder and anxiety) and in their comorbidity. However, the mechanisms involving the LC that underlie these effects have not been fully elucidated, in part owing to the technical difficulties inherent in exploring such a tiny nucleus. However, novel research tools are now available that have helped redefine the LC system, moving away from the traditional view of LC as a homogeneous structure that exerts a uniform influence on neural activity. Indeed, innovative techniques such as DREADDs (designer receptors exclusively activated by designer drugs) and optogenetics have demonstrated the functional heterogeneity of LC, and novel magnetic resonance imaging applications combined with pupillometry have opened the way to evaluate LC activity in vivo. This review aims to bring together the data available on the efferent activity of the LC-noradrenergic system in relation to pain and its comorbidity with anxiodepressive disorders. Acute pain triggers a robust LC stress response, producing spinal cord-mediated endogenous analgesia while promoting aversion, vigilance, and threat detection through its ascending efferents. However, this protective biological system fails in chronic pain, and LC activity produces pain facilitation, anxiety, increased aversive memory, and behavioral despair, acting at the medulla, prefrontal cortex, and amygdala levels. Thus, the activation/deactivation of specific LC projections contributes to different behavioral outcomes in the shift from acute to chronic pain.

Depression is a multifactorial mood disorder with a high prevalence worldwide. Until now, treatments for depression have focused on the inhibition of monoaminergic reuptake sites, which augment the bioavailability of monoamines in the CNS. Advances in drug discovery have widened the therapeutic options with the synthesis of so-called selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine. The aim of this case history is to describe and discuss the pharmacokinetic and pharmacodynamic profiles of fluoxetine, including its acute effects and the adaptive changes induced after long-term treatment. Furthermore, the authors review the effect of fluoxetine on neuroplasticity and adult neurogenesis. In addition, the article summarises the preclinical behavioural data available on fluoxetine's effects on depressive-like behaviour, anxiety and cognition as well as its effects on other diseases. Finally, the article describes the seminal studies validating the antidepressant effects of fluoxetine. Fluoxetine is the first selective SSRI that has a recognised clinical efficacy and safety profile. Since its discovery, other molecules that mimic its mechanism of action have been developed, commencing a new age in the treatment of depression. Fluoxetine has also demonstrated utility in the treatment of other disorders for which its prescription has now been approved.

Background: There is a pressing need to identify novel pathophysiological pathways relevant to depression that can help to reveal targets for the development of new medications. Toll-like receptor 4 (TLR-4) has a regulatory role in the brain's response to stress. Psychological stress may compromise the intestinal barrier, and increased gastrointestinal permeability with translocation of lipopolysaccharide (LPS) from Gram-negative bacteria may play a role in the pathophysiology of major depression. Methods: Adult male Sprague-Dawley rats were subjected to chronic mild stress (CMS) or CMS+intestinal antibiotic decontamination (CMS+ATB) protocols. Levels of components of the TLR-4 signaling pathway, of LPS and of different inflammatory, oxidative/nitrosative and anti-inflammatory mediators were measured by RT-PCR, western blot and/or ELISA in brain prefrontal cortex. Behavioral despair was studied using Porsolt's test. Results: CMS increased levels of TLR-4 and its co-receptor MD-2 in brain as well as LPS and LPS-binding protein in plasma. In addition, CMS also increased interleukin (IL)-1β, COX-2, PGE₂ and lipid peroxidation levels and reduced levels of the anti-inflammatory prostaglandin 15d-PGJ₂ in brain tissue. Intestinal decontamination reduced brain levels of the pro-inflammatory parameters and increased 15d-PGJ₂, however this did not affect depressive-like behavior induced by CMS. Conclusions: Our results suggest that LPS from bacterial translocation is responsible, at least in part, for the TLR-4 activation found in brain after CMS, which leads to release of inflammatory mediators in the CNS. The use of Gram-negative antibiotics offers a potential therapeutic approach for the adjuvant treatment of depression.

Introduction: Tramadol is an opioid drug that, unlike classic opioids, also modulates the monoaminergic system by inhibiting noradrenergic and serotoninergic reuptake. For this reason, tramadol is considered an atypical opioid. These special pharmacological characteristics have made tramadol one of the most commonly prescribed analgesic drugs to treat moderate to severe pain. Areas covered: The aim of this review is to provide a historical description of the biochemistry, pharmacokinetics and particularly, the mechanisms of action of tramadol. In addition, a summary is offered of the analgesic effects of tramadol in a variety of animal models of acute and chronic pain. Finally, clinical studies that demonstrate the efficacy and safety of tramadol in the treatment of pain are also assessed. Expert opinion: The discovery that tramadol combines opioid and monoaminergic effects represented a milestone in the evolution of pain treatment. Given its ‘mild effect’ on opioid receptors, tramadol induces fewer side effects than classic opioids. Tramadol produces satisfactory analgesia against various types of pain and it is currently approved for the treatment of moderate to severe pain. Thus, the combination of monoamine and opioid mechanisms opens new avenues for the design of innovative analgesics.

Pain affects both sensory and emotional aversive responses, often provoking anxiety-related diseases when chronic. However, the neural mechanisms underlying the interactions between anxiety and chronic pain remain unclear. We characterized the sensory, emotional, and cognitive consequences of neuropathic pain (chronic constriction injury) in a rat model. Moreover, we determined the role of the locus coeruleus (LC) neurons that project to the basolateral amygdala (BLA) using a DREADD (designer receptor exclusively activated by designer drugs). Chronic constriction injury led to sensorial hypersensitivity in both the short term and long term. Otherwise, long-term pain led to an anxiety-like profile (in the elevated zero maze and open field tests), as well as increased responses to learn aversive situations (in the passive avoidance and fear conditioning tests) and an impairment of nonemotional cognitive tasks (in the novel object recognition and object pattern of separation tests). Chemogenetic blockade of the LC-BLA pathway and intra-BLA or systemic antagonism of beta-adrenergic receptors abolished both long-term pain-induced anxiety and enhanced fear learning. By contrast, chemogenetic activation of this pathway induced anxiety-like behaviors and enhanced the aversive learning and memory index in sham animals, although it had little effect on short- and long-term chronic constriction injury animals. Interestingly, modulation of LC-BLA activity did not modify sensorial perception or episodic memory. Our results indicate that dimensions associated with pain are processed by independent pathways and that there is an overactivation of the LC-BLA pathway when anxiety and chronic pain are comorbid, which involves the activity of beta-adrenergic receptors.

Background: Chronic pain and depression are two complex states with sensory/somatic and emotional components, and they may mutually exacerbate one another in conditions of comorbidity, leading to a poorer prognosis. Methods: The authors have evaluated the sensory and emotional components in a rat model combining chronic constriction injury (CCI, a model of chronic neuropathic pain) with unpredictable chronic mild stress (CMS, an experimental model of depression). In addition, the phosphorylation/activation of the extracellular signal-regulated kinases 1 and 2 and neuronal density was also evaluated in the anterior cingulate cortex. Four groups were tested: sham-control, sham-CMS, CCI-control, and CCI-CMS. Results: CMS selectively heightens aversion to painful experiences in animals subjected to CCI, as measured in the place escape/avoidance test at 20, 25, and 30 min (CCI-CMS (mean±SEM): 75.68±3.32, 66.75±4.70, 77.54±3.60 vs. CCI-control: 44.66±6.07, 43.17±6.92, 52.83±5.92, respectively), in conjunction with an increase in the accumulation of phosphorylation/activation of the extracellular signal-regulated kinases (CCI-CMS: 4.17±0.52 vs. sham-control: 0.96±0.05) and a decrease in neuronal density in the anterior cingulate cortex. In contrast, chronic pain did not exacerbate the characteristic profile of depression (anhedonia and behavioral despair) in rats subjected to CMS. Furthermore, depression enhances the perception of some specific modalities of sensorial pain such as cold allodynia but has no influence on mechanical threshold. Conclusions: These findings support the theory that depression leads to emotional dysfunction in the interpretation of pain in patients suffering chronic pain. In addition, combined animal models of pain-depression may provide a valuable tool to study the comorbidity of pain and depression.