There is no doubt that pain is one of the most important systems for survival. Even though we all feel pain, surprisingly little is known about pain mechanisms. Indeed, there are many outstanding fundamental questions in pain research, such as where acute pain is encoded in the brain, how pain competes with other processes. To further complicate matters, chronic pain is very different from acute or experimental pain. Chronic pain, defined as pain that persists longer than 3 months, and persists even after normal healing, is often associated with depression and anxiety, and abnormal brain structure and function1. One of the most important outstanding questions is how pain transitions from an acute, alarm state, to a disease chronic state.
A new study by Ren and colleagues2 in Nature Neuroscience provides novel evidence in rodents that the nucleus accumbens (NAcc), part of the ventral striatum – a region densely populated by dopamine receptors and typically associated with the processing hedonic stimuli and developing motor programs – is involved in the chronification of neuropathic pain. Neuropathic pain is pain caused by nerve injury. The NAcc is a subregion of a set of brain regions called the basal ganglia – which just means a set of neurons that form structures in the core of the brain (see Figure 1). The basal ganglia are thought to be a more primitive part of the brain, and thus serve primitive functions such as sensation, emotion (limbic), motor responses. These functions are thought to be modulated by cortical inputs, and have evolved to underlie most brain functions.
The NAcc is composed of two subregions: the core and the shell. The shell of the NAcc is thought to be a limbic-motor interface, and is associated with addiction. Indeed, it receives dense input from the subgenual anterior cingulate cortex (sgACC)3, which is related to depression [this is the ventral area of ACC that projects to VS (ventral striatum) in Figure 1]. It is believed that limbic pathways can modulate motor pathways through the NAcc.
Figure 1: Schematic illustrating key structures and pathways of the basal ganglia. Note: brainstem motor connections are not illustrated to simplify the figure. Cd, caudate nucleus; ACC, anterior cingulate cortex; dPFC, dorsal prefrontal cortex; GP, globus pallidus; LHb, lateral habenula; OFC, orbital frontal cortex; Pu, putamen; RMTg, rostromedial tegmental nucleus; SN, substantia nigra; STN, subthalamic n; Thal, thalamus; VP, ventral pallidum; VS, ventral striatum; VTA, ventral tegmental area. (Source 4 Suzanne Haber is the penultimate expert on the basal ganglia).
The study by Ren et al showed increased excitability only in cells specific to the shell of the NAcc (spiny projection neurons in the indirect pathway), which altered their connectivity. Furthermore, a common and widely used behavioural proxy measure of pain in rodent models of chronic pain is a withdrawal of the injured paw to a fine filament. Normally, this filament wouldn’t cause pain, and the animal wouldn’t withdraw their paw – but when injured, the paw becomes sensitive to light touch (much like a sunburn – a state called allodynia). The authors found that by ablating the shell of the NAcc, the rodents no longer withdrew their paw to the touch stimulus. To further demonstrate the link between allodynia and the NAcc, they then chemically activated these neurons and showed enhanced allodynia in rodents. This effect was blunted with a combination of an NSAID (Naproxen – also known as Aleve) and L-DOPA (a molecule that can be metabolized to make dopamine in the brain).
These findings are compelling as they corroborate recent evidence that the NAcc is involved in pain chronification of back pain in humans. However, another study in Nature Neuroscience showed that the direct and indirect striatal pathways may not be present in rodents5. So, there is converging evidence between human and rodent chronic pain mechanisms, but these should be interpreted with caution until the circuitry is established. There is, however, no doubt, that some pain behaviours engage the NAcc, and the study provides new avenues of research in neuropathic pain treatment.
- Davis, K. D. & Moayedi, M. Central Mechanisms of Pain Revealed Through Functional and Structural MRI. J Neuroimmune Pharmacol 8, 518-534 (2013).
- Ren, W. et al. The indirect pathway of the nucleus accumbens shell amplifies neuropathic pain. Nat Neurosci (2015).
- Haber, S. N., Kunishio, K., Mizobuchi, M. & Lynd-Balta, E. The orbital and medial prefrontal circuit through the primate basal ganglia. J Neurosci 15, 4851-4867 (1995).
- Haber, S. N. The place of dopamine in the cortico-basal ganglia circuit. Neuroscience 282C, 248-257 (2014).
- Kupchik, Y. M. et al. Coding the direct/indirect pathways by D1 and D2 receptors is not valid for accumbens projections. Nat Neurosci 18, 1230-1232 (2015).