Nerve Injury Triggers Time-dependent Activation of the Locus Coeruleus, Influencing Spontaneous Pain-like Behavior in Rats.

BACKGROUND: Dynamic changes in neuronal activity and in noradrenergic locus coeruleus (LC) projections have been proposed during the transition from acute to chronic pain. Thus, the authors explored the cellular cFos activity of the LC and its projections in conjunction with spontaneous pain-like behavior in neuropathic rats. METHODS: Tyrosine hydroxylase:Cre and wild-type Long-Evans rats, males and females, were subjected to chronic constriction injury (CCI) for 2 (short-term, CCI-ST) or 30 days (long-term, CCI-LT), evaluating cFos and Fluoro-Gold expression in the LC, and its projections to the spinal cord (SC) and rostral anterior cingulate cortex (rACC). These tests were carried out under basal conditions (unstimulated) and after noxious mechanical stimulation. LC activity was evaluated through chemogenetic and pharmacologic approaches, as were its projections, in association with spontaneous pain-like behaviors. RESULTS: CCI-ST enhanced basal cFos expression in the LC and in its projection to the SC, which increased further after noxious stimulation. Similar basal activation was found in the neurons projecting to the rACC, although this was not modified by stimulation. Strong basal cFos expression was found in CCI-LT, specifically in the projection to the rACC, which was again not modified by stimulation. No cFos expression was found in the CCI-LT LCipsilateral (ipsi)/contralateral (contra)→SC. Chemogenetics showed that CCI-ST is associated with greater spontaneous pain-like behavior when the LCipsi is blocked, or by selectively blocking the LCipsi→SC projection. Activation of the LCipsi or LCipsi/contra→SC dampened pain-like behavior. Moreover, Designer Receptor Exclusively Activated by Designer Drugs (DREADDs)-mediated inactivation of the CCI-ST LCipsi→rACC or CCI-LT LCipsi/contra→rACC pathway, or intra-rACC antagonism of α-adrenoreceptors, also dampens pain-like behavior. CONCLUSIONS: In the short term, activation of the LC after CCI attenuates spontaneous pain-like behaviors via projections to the SC while increasing nociception via projections to the rACC. In the long term, only the projections from the LC to the rACC contribute to modulate pain-like behaviors in this model.

Chemogenetic activation of locus coeruleus neurons ameliorates the severity of multiple sclerosis.

BACKGROUND: Most current disease-modifying therapies approved for multiple sclerosis (MS) are immunomodulatory drugs that counteract the aberrant activity of the immune system. Hence, new pharmacological interventions that drive anti-inflammatory activity and neuroprotection would represent interesting alternative therapeutic approaches or complementary strategies to treat progressive forms of MS. There is evidence of reduced noradrenaline levels and alterations to locus coeruleus (LC) noradrenergic neurons in MS patients, as well as in animal models of this disease, potentially factors contributing to the pathophysiology. Drugs that enhance noradrenaline appear to have some beneficial effects in MS, suggesting their potential to dampen the underlying pathology and disease progression. METHODS: Therefore, we explored the consequences of chronic LC noradrenergic neurons activation by chemogenetics in experimental autoimmune encephalomyelitis (EAE) mice, the most widely used experimental model of MS. LC activation from the onset or the peak of motor symptoms was explored as two different therapeutic approaches, assessing the motor and non-motor behavioral changes as EAE progresses, and studying demyelination, inflammation and glial activation in the spinal cord and cerebral cortex during the chronic phase of EAE. RESULTS: LC activation from the onset of motor symptoms markedly alleviated the motor deficits in EAE mice, as well as their anxiety-like behavior and sickness, in conjunction with reduced demyelination and perivascular infiltration in the spinal cord and glial activation in the spinal cord and prefrontal cortex (PFC). When animals exhibited severe paralysis, LC activation produced a modest alleviation of EAE motor symptoms and it enhanced animal well-being, in association with an improvement of the EAE pathology at the spinal cord and PFC level. Interestingly, the reduced dopamine beta-hydroxylase expression associated with EAE in the spinal cord and PFC was reversed through chemogenetic LC activation. CONCLUSION: Therefore, clear anti-inflammatory and neuroprotective effects were produced by the selective activation of LC noradrenergic neurons in EAE mice, having greater benefits when LC activation commenced earlier. Overall, these data suggest noradrenergic LC neurons may be targets to potentially alleviate some of the motor and non-motor symptoms in MS.

Sexual differences in locus coeruleus neurons and related behavior in C57BL/6J mice.

BACKGROUND: In addition to social and cultural factors, sex differences in the central nervous system have a critical influence on behavior, although the neurobiology underlying these differences remains unclear. Interestingly, the Locus Coeruleus (LC), a noradrenergic nucleus that exhibits sexual dimorphism, integrates signals that are related to diverse activities, including emotions, cognition and pain. Therefore, we set-out to evaluate sex differences in behaviors related to LC nucleus, and subsequently, to assess the sex differences in LC morphology and function. METHODS: Female and male C57BL/6J mice were studied to explore the role of the LC in anxiety, depressive-like behavior, well-being, pain, and learning and memory. We also explored the number of noradrenergic LC cells, their somatodendritic volume, as well as the electrophysiological properties of LC neurons in each sex. RESULTS: While both male and female mice displayed similar depressive-like behavior, female mice exhibited more anxiety-related behaviors. Interestingly, females outperformed males in memory tasks that involved distinguishing objects with small differences and they also showed greater thermal pain sensitivity. Immunohistological analysis revealed that females had fewer noradrenergic cells yet they showed a larger dendritic volume than males. Patch clamp electrophysiology studies demonstrated that LC neurons in female mice had a lower capacitance and that they were more excitable than male LC neurons, albeit with similar action potential properties. CONCLUSIONS: Overall, this study provides new insights into the sex differences related to LC nucleus and associated behaviors, which may explain the heightened emotional arousal response observed in females.

Exploring sex differences in the brain is important to understand the impact of such differences in pathological conditions characterized by gender bias, as well as their therapeutic implications. In this manuscript, we examined sex differences in the mouse locus coeruleus (LC) and how this might affect related behaviours. The LC is a sexually dimorphic nucleus that integrates signals associated with attention, anxiety, stress, arousal, pain, memory and learning. Our findings reveal that female mice exhibit more intense anxiety-related behaviors but that they perform better than males in recognizing small differences between objects. Additionally, we found pronounced sex differences in the LC, which contained fewer noradrenergic cells in females, with a larger dendritic volume and displaying enhanced cell excitability. These differences in the LC, a nucleus that fulfils a pivotal role in stress and pain, could be important for understanding the higher prevalence of stress-related disorders in women, such as anxiety and depression, but also of chronic pain. Hence, it is clearly important to consider sex differences in both preclinical and clinical research studies that attempt to understand pathologies related to these phenomena.

Altered expression of vesicular glutamate transporter-2 and cleaved caspase-3 in the locus coeruleus of nerve-injured rats.

Neuropathic pain is a debilitating chronic condition provoked by a lesion in the nervous system and it induces functional alterations to the noradrenergic locus coeruleus (LC), affecting distinct dimensions of pain, like sensorial hypersensitivity, pain-induced depression, and anxiety. However, the neurobiological changes induced by nerve damage in the LC remain unclear. Here, we analyzed excitatory and inhibitory inputs to the LC, as well as the possible damage that noradrenergic neurons suffer after the induction of neuropathic pain through chronic constriction injury (CCI). Neuropathic pain was induced in male Sprague-Dawley rats, and the expression of the vesicular glutamate transporter 1 or 2 (VGLUT1 or VGLUT2), vesicular GABA transporter (VGAT), and cleaved caspase-3 (CC3) was analyzed by immunofluorescence 7 (CCI7d) or 28 days after the original lesion (CCI28d). While no significant differences in the density of VGLUT1 puncta were evident, CCI7d induced a significant increase in the perisomatic VGLUT2/VGAT ratio relative to Sham-operated and CCI28d animals. By contrast, when the entire region of LC is evaluated, there was a significant reduction in the density of VGLUT2 puncta in CCI28d animals, without changes in VGLUT2/VGAT ratio relative to the CCI7d animals. Additionally, changes in the noradrenergic soma size, and a lower density of mitochondria and lysosomes were evident in CCI28d animals. Interestingly, enhanced expression of the apoptotic marker CC3 was also evident in the CCI28d rats, mainly co-localizing with glial fibrillary acidic protein but not with any neuronal or noradrenergic marker. Overall, short-term pain appears to lead to an increase of markers of excitatory synapses in the perisomatic region of noradrenergic cells in the LC, an effect that is lost after long-term pain, which appears to activate apoptosis.

The Role of the Locus Coeruleus in Pain and Associated Stress-Related Disorders.

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.

Nerve injury induces transient locus coeruleus activation over time: role of the locus coeruleus-dorsal reticular nucleus pathway.

ABSTRACT: The transition from acute to chronic pain results in maladaptive brain remodeling, as characterized by sensorial hypersensitivity and the ensuing appearance of emotional disorders. Using the chronic constriction injury of the sciatic nerve as a model of neuropathic pain in male Sprague-Dawley rats, we identified time-dependent plasticity of locus coeruleus (LC) neurons related to the site of injury, ipsilateral (LCipsi) or contralateral (LCcontra) to the lesion, hypothesizing that the LC→dorsal reticular nucleus (DRt) pathway is involved in the pathological nociception associated with chronic pain. LCipsi inactivation with lidocaine increased cold allodynia 2 days after nerve injury but not later. However, similar blockade of LCcontra reduced cold allodynia 7 and 30 days after inducing neuropathy but not earlier. Furthermore, lidocaine blockade of the LCipsi or LCcontra reversed pain-induced depression 30 days after neuropathy. Long-term pain enhances phosphorylated cAMP-response element binding protein expression in the DRtcontra but not in the DRtipsi. Moreover, inactivation of the LCcontra→DRtcontra pathway using dual viral-mediated gene transfer of designer receptor exclusively activated by designer drugs produced consistent analgesia in evoked and spontaneous pain 30 days postinjury. This analgesia was similar to that produced by spinal activation of α2-adrenoreceptors. Furthermore, chemogenetic inactivation of the LCcontra→DRtcontra pathway induced depressive-like behaviour in naïve animals, but it did not modify long-term pain-induced depression. Overall, nerve damage activates the LCipsi, which temporally dampens the neuropathic phenotype. However, the ensuing activation of a LCcontra→DRtcontra facilitatory pain projection contributes to chronic pain, whereas global bilateral LC activation contributes to associated depressive-like phenotype.

Pain and depression comorbidity causes asymmetric plasticity in the locus coeruleus neurons.

There is strong comorbidity between chronic pain and depression, although the neural circuits and mechanisms underlying this association remain unclear. By combining immunohistochemistry, tracing studies and western blotting, with the use of different DREADDS (designer receptor exclusively activated by designer drugs) and behavioural approaches in a rat model of neuropathic pain (chronic constriction injury), we explore how this comorbidity arises. To this end, we evaluated the time-dependent plasticity of noradrenergic locus coeruleus neurons relative to the site of injury: ipsilateral (LCipsi) or contralateral (LCcontra) locus coeruleus at three different time points: short (2 days), mid (7 days) and long term (30-35 days from nerve injury). Nerve injury led to sensorial hypersensitivity from the onset of injury, whereas depressive-like behaviour was only evident following long-term pain. Global chemogenetic blockade of the LCipsi system alone increased short-term pain sensitivity while the blockade of the LCipsi or LCcontra relieved pain-induced depression. The asymmetric contribution of locus coeruleus modules was also evident as neuropathy develops. Hence, chemogenetic blockade of the LCipsi→spinal cord projection, increased pain-related behaviours in the short term. However, this lateralized circuit is not universal as the bilateral chemogenetic inactivation of the locus coeruleus-rostral anterior cingulate cortex pathway or the intra-rostral anterior cingulate cortex antagonism of alpha1- and alpha2-adrenoreceptors reversed long-term pain-induced depression. Furthermore, chemogenetic locus coeruleus to spinal cord activation, mainly through LCipsi, reduced sensorial hypersensitivity irrespective of the time post-injury. Our results indicate that asymmetric activation of specific locus coeruleus modules promotes early restorative analgesia, as well as late depressive-like behaviour in chronic pain and depression comorbidity.

Pain in neuropsychiatry: Insights from animal models.

Pain is the most common symptom reported in clinical practice, meaning that it is associated with many pathologies as either the origin or a consequence of other illnesses. Furthermore, pain is a complex emotional and sensorial experience, as the correspondence between pain and body damage varies considerably. While these issues are widely acknowledged in clinical pain research, until recently they have not been extensively considered when exploring animal models, important tools for understanding pain pathophysiology. Interestingly, chronic pain is currently considered a risk factor to suffer psychiatric disorders, mainly stress-related disorders like anxiety and depression. Conversely, pain appears to be altered in many psychiatric disorders, such as depression, anxiety and schizophrenia. Thus, pain and psychiatric disorders have been linked in epidemiological and clinical terms, although the neurobiological mechanisms involved in this pathological bidirectional relationship remain unclear. Here we review the evidence obtained from animal models about the co-morbidity of pain and psychiatric disorders, placing special emphasis on the different dimensions of pain.

Opioid receptors mRNAs expression and opioids agonist-dependent G-protein activation in the rat brain following neuropathy.

Potent opioid-based therapies are often unsuccessful in promoting satisfactory analgesia in neuropathic pain. Moreover, the side effects associated with opioid therapy are still manifested in neuropathy-like diseases, including tolerance, abuse, addiction and hyperalgesia, although the mechanisms underlying these effects remain unclear. Studies in the spinal cord and periphery indicate that neuropathy alters the expression of mu-[MOP], delta-[DOP] or kappa-[KOP] opioid receptors, interfering with their activity. However, there is no consensus as to the supraspinal opioidergic modulation provoked by neuropathy, the structures where the sensory and affective-related pain components are processed. In this study we explored the effect of chronic constriction of the sciatic nerve (CCI) over 7 and 30 days (CCI-7d and CCI-30d, respectively) on MOP, DOP and KOP mRNAs expression, using in situ hybridization, and the efficacy of G-protein stimulation by DAMGO, DPDPE and U-69593 (MOP, DOP and KOP specific agonists, respectively), using [35S]GTPγS binding, within opioid-sensitive brain structures. After CCI-7d, CCI-30d or both, opioid receptor mRNAs expression was altered throughout the brain: MOP - in the paracentral/centrolateral thalamic nuclei, ventral posteromedial thalamic nuclei, superior olivary complex, parabrachial nucleus [PB] and posterodorsal tegmental nucleus; DOP - in the somatosensory cortex [SSC], ventral tegmental area, caudate putamen [CPu], nucleus accumbens [NAcc], raphe magnus [RMg] and PB; and KOP - in the locus coeruleus. Agonist-stimulated [35S]GTPγS binding was altered following CCI: MOP - CPu and RMg; DOP - prefrontal cortex [PFC], SSC, RMg and NAcc; and KOP - PFC and SSC. Thus, this study shows that several opioidergic circuits in the brain are recruited and modified following neuropathy.

Chemogenetic Silencing of the Locus Coeruleus-Basolateral Amygdala Pathway Abolishes Pain-Induced Anxiety and Enhanced Aversive Learning in Rats.

BACKGROUND: 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. METHODS: 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). RESULTS: 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. CONCLUSIONS: 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.

Monoamines as Drug Targets in Chronic Pain: Focusing on Neuropathic Pain.

Monoamines are involved in regulating the endogenous pain system and indeed, peripheral and central monoaminergic dysfunction has been demonstrated in certain types of pain, particularly in neuropathic pain. Accordingly, drugs that modulate the monaminergic system and that were originally designed to treat depression are now considered to be first line treatments for certain types of neuropathic pain (e.g., serotonin and noradrenaline (and also dopamine) reuptake inhibitors). The analgesia induced by these drugs seems to be mediated by inhibiting the reuptake of these monoamines, thereby reinforcing the descending inhibitory pain pathways. Hence, it is of particular interest to study the monoaminergic mechanisms involved in the development and maintenance of chronic pain. Other analgesic drugs may also be used in combination with monoamines to facilitate descending pain inhibition (e.g., gabapentinoids and opioids) and such combinations are often also used to alleviate certain types of chronic pain. By contrast, while NSAIDs are thought to influence the monoaminergic system, they just produce consistent analgesia in inflammatory pain. Thus, in this review we will provide preclinical and clinical evidence of the role of monoamines in the modulation of chronic pain, reviewing how this system is implicated in the analgesic mechanism of action of antidepressants, gabapentinoids, atypical opioids, NSAIDs and histaminergic drugs.

Opioid Activity in the Locus Coeruleus Is Modulated by Chronic Neuropathic Pain.

Pain affects both sensory and emotional aversive responses, often provoking depression and anxiety-related conditions when it becomes chronic. As the opioid receptors in the locus coeruleus (LC) have been implicated in pain, stress responses, and opioid drug effects, we explored the modifications to LC opioid neurotransmission in a chronic constriction injury (CCI) model of short- and long-term neuropathic pain (7 and 30 days after nerve injury). No significant changes were found after short-term CCI, yet after 30 days, CCI provoked an up-regulation of cAMP (cyclic 5'-adenosine monophosphate), pCREB (phosphorylated cAMP response element binding protein), protein kinase A, tyrosine hydroxylase, and electrical activity in the LC, as well as enhanced c-Fos expression. Acute mu opioid receptor desensitization was more intense in these animals, measured as the decline of the peak current caused by [Met5]-enkephalin and the reduction of forskolin-stimulated cAMP produced in response to DAMGO. Sustained morphine treatment did not markedly modify certain LC parameters in CCI-30d animals, such as [Met5]-enkephalin-induced potassium outward currents or burst activity and c-Fos rebound after naloxone precipitation, which may limit the development of some typical opioid drug-related adaptations. However, other phenomena were impaired by long-term CCI, including the reduction in forskolin-stimulated cAMP accumulation by DAMGO after naloxone precipitation in morphine dependent animals. Overall, this study suggests that long-term CCI leads to changes at the LC level that may contribute to the anxiodepressive phenotype that develops in these animals. Furthermore, opioid drugs produce complex adaptations in the LC in this model of chronic neuropathic pain.

The onset of treatment with the antidepressant desipramine is critical for the emotional consequences of neuropathic pain.

Neuropathic pain is a chronic condition that is challenging to treat. It often produces considerable physical disability and emotional distress. Patients with neuropathic pain often experience depression and anxiety both of which are known to be temporally correlated with noradrenergic dysfunction in the locus coeruleus (LC) as pain becomes chronic. Antidepressants are the first-line drug therapy for neuropathic pain, and the LC represents a potential target for such therapy. In this study, we evaluated the efficacy of the tricyclic antidepressant desipramine (DMI, a noradrenaline reuptake inhibitor) in preventing or relieving the noradrenergic impairment induced by neuropathic pain. The treatment started before or after the onset of the anxiodepressive phenotype ("early or late treatment") in adult rats subjected to chronic sciatic constriction. Electrophysiological and western blotting assays showed LC dysfunction (increased bursting activity, alpha2-adrenoceptor sensitivity, tyrosine hydroxylase, and noradrenaline transporter expression) in chronic constriction injury at long term. These noradrenergic changes were concomitant to the progression of anxiety and despair-like features. Desipramine induced efficient analgesia, and it counteracted the despair-like behavior in chronic constriction injury-DMI animals, reducing the burst rate and tyrosine hydroxylase expression. Surprisingly, "early" DMI treatment did not modify pain-induced anxiety, and it dampened pain aversion, although these phenomena were abolished when the treatment commenced after noradrenaline impairment had been established. Hence, DMI seems to produce different outcomes depending when the treatment commences, indicating that the balance between the benefits and adverse effects of DMI therapy may shift as neuropathy progresses.

Behavioral effects of combined morphine and MK-801 administration to the locus coeruleus of a rat neuropathic pain model.

The persistent activation of N-methyl-d-aspartate acid receptors (NMDARs) seems to be responsible for a series of changes in neurons associated with neuropathic pain, including the failure of opioids that act through mu-opioid receptors (MORs) to provide efficacious pain relief. As the noradrenergic locus coeruleus (LC) forms part of the endogenous analgesic system, we explored how intra-LC administration of morphine, a MORs agonist, alone or in combination with MK-801, a NMDARs antagonist, affects the sensorial and affective dimension of pain in a rat model of neuropathic pain; chronic constriction injury (CCI). Intra-LC microinjection of morphine induced analgesia in CCI rats, as evident in the von Frey and cold plate test 7 and 30 days after surgery, although it was not able to reverse pain-related aversion when evaluated using the place escape/avoidance test. However, the thermal anti-nociception produced by morphine was enhanced when it was administered to the LC of CCI animals in combination with MK-801, without altering its effects on the mechanical thresholds. Furthermore, pain-related aversion was reduced by co-administration of these agents, yet only in the short-term CCI (7 day) rats. Overall the data indicate that administration of morphine to the LC produces analgesia in nerve injured animals and that this effect is potentiated in specific pain modalities by the co-administration of MK-801. While a combination of morphine and MK-801 could reduce pain-related aversion in short-term neuropathic animals, it was ineffective in the long-term, suggesting that its sensorial effects and its influence on the affective component of pain are regulated by different mechanisms.

Noradrenergic Locus Coeruleus pathways in pain modulation.

The noradrenergic system is crucial for several activities in the body, including the modulation of pain. As the major producer of noradrenaline (NA) in the central nervous system (CNS), the Locus Coeruleus (LC) is a nucleus that has been studied in several pain conditions, mostly due to its strategic location. Indeed, apart from a well-known descending LC-spinal pathway that is important for pain control, an ascending pathway passing through this nucleus may be responsible for the noradrenergic inputs to higher centers of the pain processing, such as the limbic system and frontal cortices. Thus, the noradrenergic system appears to modulate different components of the pain experience and accordingly, its manipulation has distinct behavioral outcomes. The main goal of this review is to bring together the data available regarding the noradrenergic system in relation to pain, particularly focusing on the ascending and descending LC projections in different conditions. How such findings influence our understanding of these conditions is also discussed.

Effect of tapentadol on neurons in the locus coeruleus.

Tapentadol is a novel centrally acting drug that combines mu-opioid receptor (MOR) agonism and noradrenaline reuptake inhibition (NRI), producing analgesic effects in various painful conditions. We investigated the acute effects of tapentadol in the locus coeruleus (LC), a central nucleus regulated by the noradrenergic and opioid systems that is critical in pain modulation. In single-unit extracellular recordings of LC neurons from anaesthetized male Sprague-Dawley rats, tapentadol clearly inhibited the spontaneous electrophysiological activity of LC neurons in a dose-dependent manner (ED50 = 0.8 mg/kg). This inhibitory effect was reversed by RX821002 (an alpha2-adrenoceptor antagonist) and naloxone (a mu-opioid receptor antagonist) by 96.7% and 28.2%, respectively. Pretreatment with RX821002, N-ethoxycarbonyl-2-ethoxy-1-2-dihydroquinoline (EEDQ, an irreversible alpha2-adrenoceptor antagonist) or naloxone shifted the tapentadol dose-effect curve to the right (ED50 = 2.2 mg/kg, 2.0 mg/kg and 2.1 mg/kg, respectively). Furthermore, tapentadol inhibited the LC response to mechanical stimulation of the hindpaw in a dose-dependent manner. In summary, we demonstrate that acute administration of tapentadol inhibits LC neurons in vivo, mainly due to the activation of alpha2-adrenoceptors. These data suggest that both the noradrenergic and opioid systems participate in the inhibitory effect of tapentadol on LC neurons, albeit to different extents, which may account for its potent analgesic effect and mild opioidergic side-effects.

Chronic pain leads to concomitant noradrenergic impairment and mood disorders.

BACKGROUND: Patients suffering chronic pain are at high risk of suffering long-lasting emotional disturbances characterized by persistent low mood and anxiety. We propose that this might be the result of a functional impairment in noradrenergic circuits associated with locus coeruleus (LC) and prefrontal cortex, where emotional and sensorial pain processes overlap. METHODS: We used a chronic constriction injury of sciatic nerve as a model of neuropathic pain in male Sprague-Dawley rats to assess the time-dependent changes that might potentially precipitate mood disorders (2, 7, 14, and 28 days after injury). This was measured through a combination of behavioral, electrophysiological, microdialysis, immunohistochemical, and Western blot assays. RESULTS: As expected, nerve injury produced an early and stable decrease in sensorial pain threshold over the testing period. By contrast, long-term neuropathic pain (28 days after injury) resulted in an inability to cope with stressful situations, provoking depressive and anxiogenic-like behaviors, even more intense than the aversiveness associated with pain perception. The onset of these behavioral changes coincided with irruption of noradrenergic dysfunction, evident as: an increase in LC bursting activity; in tyrosine hydroxylase expression and that of the noradrenaline transporter; and enhanced expression and sensitivity of α2-adrenoceptors in the LC. CONCLUSIONS: Long-term neuropathic pain leads to anxio-depressive-like behaviors that are more predominant than the aversion of a painful experience. These changes are consistent with the impairment of noradrenergic system described in depressive disorders.