Chronic Pain Leads to Concomitant Noradrenergic Impairment and Mood Disorders

doi:10.1016/j.biopsych.2012.06.033

Biological Psychiatry

Volume 73, Issue 1, 1 January 2013, Pages 54-62

https://doi.org/10.1016/j.biopsych.2012.06.033 Get rights and content

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.

Section snippets

Animals

Two hundred forty-three male Sprague-Dawley rats (200–250 g at the beginning of the experiments) were used for these studies. Animals were housed in groups of four in polycarbonate cages under standard laboratory conditions (22 ± 1°C, 12-hour light/dark cycles, lights on at 8:00 am, food and water ad libitum). All the experimental protocols were approved by the Committee for Animal Experimentation at the University of Cádiz (Spain) and complied with the International Association for the Study

Nociceptive Behavioral Response

Pain behaviors were evident in CCI rats as early as 2 days after surgery, and they remained stable for up to 28 days post-surgery. Hence, the nociceptive threshold of these animals in response to mechanical von Frey filament stimulation, paw pressure, and radiant heat was significantly lower than that of sham-operated animals (p < .001) (Figure 1A, C, and D). Furthermore, in the cold-plate test (Figure 1B), the CCI rats lifted their paws very frequently, reflecting cold allodynia, whereas cold

Discussion

The present study shows that neuropathic pain produces a significant and stable decrease in the pain threshold over the period tested, coupled to an anxiogenic and depressive-like state 28 days after pain induction but not earlier. These emotional changes temporally coincided with marked modifications to noradrenergic LC neurons, such as increased TH and NAT expression, and α2-adrenoceptor hypersensitivity that influences LC firing and noradrenaline release in terminal areas like the PFC.

Pain

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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.
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Archival ReportChronic Pain Leads to Concomitant Noradrenergic Impairment and Mood Disorders

Background

Methods

Results

Conclusions

Section snippets

Animals

Nociceptive Behavioral Response

Discussion

Biol Psychiatry

J Pain Symptom Manage

Biol Psychiatry

Biol Psychiatry

Brain Res Brain Res Rev

Prog Brain Res

Pain

Pain

Eur J Pharmacol

Pain

Pain

Neuropharmacology

J Biol Chem

Pain

Pain

Pain

Eur J Pharmacol

Eur Neuropsychopharmacol

Brain Res Mol Brain Res

Exp Neurol

Biol Psychiatry

J Biol Chem

Brain Res

Brain Res

Eur J Pharmacol

Prog Neurobiol

Eur J Pain

Arch Phys Med Rehabil

Biol Psychiatry

Biol Psychiatry

Trends Pharmacol Sci

Depression and pain comorbidity: A literature review

Arch Intern Med

Chronic pain and psychopathology: Research findings and theoretical considerations

Psychosom Med

Psychological and neural mechanisms of the affective dimension of pain

Science

Archival Report
Chronic Pain Leads to Concomitant Noradrenergic Impairment and Mood Disorders