Chronic Pain Leads to Concomitant Noradrenergic Impairment and Mood Disorders.

This is an interesting work that uses a neuropathic pain model, produced by chronic constriction injury (CCI) of sciatic nerve, to test the hypothesis that altered locus coeruleus (LC) function might promote the depressive and anxiogenic behavior in chronic pain conditions. As explained in this paper, LC is regarded as a part of central “stress circuitry” that is involved in pathogenesis of depression and anxiety disorders.  In this model of neuropathic pain, pain behavior, measured by Von Frey stimulation, paw pressure and radiant heat, was evident after two days, and was stable for up to 28 days. In this study, a depression-like state was indicated by passive coping behavior through monitoring the state of immobility in a modified forced swim test. The state of anxiety was monitored by reduced time spent in open quadrants in an elevated zero maze. In addition, aversion to pain or to a mild anxiogenic place (bright) was compared by studying the animals' preference for dark place, nonanxiogenic area, where the injured paw is stimulated versus anxiogenic bright area where the noninjured paw is stimulated. In the animals 7 days post-CCI, aversion to painful stimulation was greater than aversion to anxiogenic bright compartment. This was markedly reversed in rats 28 days post-CCI, which spent markedly greater time in dark (non-anxiogenic) as compared to sham-operated rats, even as the stimulation of the injured paw occurred in dark. This, combined with other behavioral findings, such as development of coping behavior, increased states of immobility in a modified forced swim test, and decreased time spent in open compartments, indicated development of depression and anxiety-like behavior on day 28 following CCI.  Parallel biochemical and immunochemical analysis of LC tissue at 28 days in post-CCI rats shows significantly increased expression of tyrosine hydroxylase, the rate-limiting enzyme in noradrenaline biosynthesis, and of the noradrenaline transporter, indicating increased noradrenaline release, which is corroborated by electrophysiological findings presented in this paper. 

Overall this paper successfully supports the authors’ view that “long-term neuropathic pain leads to anxio-depressive-like behavior”. To understand the long-term impact of neuropathic pain, it is important to study the molecular processes underlying neuropathic pain. In this context, it will be interesting to take notice of the role of dynorphin, which is increased in the spinal cord in several models of neuropathic pain (1, 2). It has been proposed by Laughlin et al. (2) that dynorphin can interact with NMDAR at multiple sites to produce adverse effects, such as nociceptive behavior seen in chronic pain models with increased spinal cord dynorphin levels. It is also well-known that NMDAR activity can directly influence remodeling and plasticity of brain circuits (3). Therefore, in view of the findings from this paper, it is very likely that dynorphin-dependent, lasting pathophysiological processes underlying chronic pain states may directly or indirectly influence other circuits in brain, such as LC, leading to depression and anxiety-like states. One line of investigation may be to address the hypothesis that increased levels of dynorphin in the spinal cord produce alterations in brain circuits, contributing to long-term effects of neuropathic pain, leading to the development of depression and anxiety states. Moreover, the role of descending pathways in producing increased spinal cord dynorphin has been shown before (4).  It is also likely that ascending and descending pathways interact with each other at several levels, producing complex changes in brain circuits. Dynorphin expression may also influence brain circuits, such as LC, directly, which is suggested by finding dynorphin expression in axons innervating noradrenergic dendrites in LC (5). 

In their paper, Alba-Delgado et al. have provided some important directions and tools for future study of long-term adverse effects of chronic pain.

References

1. Gupta DS, Hubscher CH. Estradiol treatment prevents injury induced enhancement in spinal cord dynorphin expression. Front Physiol. 2012;3:28.

2. Laughlin TM, Larson AA, Wilcox GL. Mechanisms of induction of persistent nociception by dynorphin. J Pharmacol Exp Ther. 2001 Oct;299(1):6-11.

3. Lau CG, Zukin RS. NMDA receptor trafficking in synaptic plasticity and neuropsychiatric disorders. Nat Rev Neurosci. 2007 Jun;8(6):413-26.

4. Burgess SE, Gardell LR, Ossipov MH, Malan TP Jr, Vanderah TW, Lai J, Porreca F. Time-dependent descending facilitation from the rostral ventromedial medulla maintains, but does not initiate, neuropathic pain. J Neurosci. 2002 Jun 15;22(12): 5129-36.

5. Reyes BA, Johnson AD, Glaser JD, Commons KG, Van Bockstaele EJ. Dynorphin-containing axons directly innervate noradrenergic neurons in the rat nucleus locus coeruleus. Neuroscience. 2007 Mar 30;145(3):1077-86.