Brain mechanisms of chronic pain: critical role of translational approach

Abstract

Chronic pain is a leading cause of disability worldwide and its prevalence is likely to increase over the next decades. Treatment for chronic pain remains insufficient and therapeutical advances have not made comparable progress with that for many chronic disorders, thus amplifying the concern on the future burden of the disease. At the same time, and even after decades of intense research, the underlying pathophysiology of chronic pain remains minimally understood. We believe advancing our current understanding of chronic pain requires mechanistically explicit, hypothesis-driven, and clinically focused models. In this review we highlight some of the main findings over the last decades that have contributed to the present knowledge of brain mechanisms of chronic pain, and how such advances were possible due to a reverse translational research approach. We argue that this approach is essential in the chronic pain field, in order to generate new scientific hypotheses, probe physiological mechanisms, develop therapeutic strategies and translate findings back into promising human clinical trials.

Figure 1.

Reverse translational approach in chronic pain research. Reverse translation research starts with clinical observations, real-life patients experience and observational research studies, and works backwards to uncover the mechanistic basis of the research question. One successful example of this methodology in chronic pain research is depicted in the figure. A. The corticostriatal functional connectivity predicted transition to a chronic state with high accuracy in humans; B. This finding was replicated in a longitudinal rodent study, in-depth characterizing underlying cellular and molecular adaptive mechanisms in the NAc, and further pharmacologically manipulating this system; C. Subsequently, this approach pointed to a new therapeutic approach for managing/preventing transition from acute to chronic pain in humans, that was recently tested in a human clinical trial.

Figure 2.

Mesocorticolimbic circuitry in humans and animal models. The biological similarity between human and rodent is a powerful tool that we use to interrogate the brain circuitry underlying chronic pain and, more recently, its overlap with addiction. Brain areas involved in addiction, as the prefrontal cortex (PFC), hippocampus, nucleus accumbens (NAc), ventral tegmental area (VTA) and retro splenial cortex (RSC) are also associated with chronic pain. Studying neuroadaptations in animal and humans’ models of pain and addiction offer a heuristic opportunity to explore its pathophysiology and interactions.

Figure 3.

Chronic pain leads to large-scale and local changes in brain functional connectivity in both humans and rodents. A. Chronic back pain (CBP), Osteoarthritis (OA) and Chronic Regional Pain Syndrome (CRPS) show similar disruption in rank-order that permeates the whole brain architecture. B. SNI rats (27 days after injury) also show rank-order disruption when compared with sham surgery rats. This disruption is again generalized and in similar magnitude to the findings in humans. C. Despite large-scale changes in functional architecture, the connectivity of specific brain regions to the rest of the brain are upregulated (red, upper panel: right thalamus and left hippocampus), or downregulated (blue, upper panel: supplementary motor area, superior parietal lobule) across chronic pain conditions. Some of these changes are specific to the chronic pain condition as illustrated in the bottom panel. D. Similar to human data, SNI rats show localized changes in functional connectivity.

Figure 4.

Mesocorticolimbic circuitry, central to reward and motivation, has been implicated in the development, amplification and persistence of chronic pain, both in animal models and human subjects. A. The strength of information exchange (functional connectivity) between the nucleus accumbens (NAc; green) and medial prefrontal cortex (mPFC) is predictive of the transition from acute to chronic low back pain. B. 28 days after SNI, functional connectivity of the NAc core and shell to Caudate, Putamen, Insula and S1/2 brain areas was reduced, compared to sham animals. C. Intra-corticolimbic white matter connectivity of the medial PFC-amygdala-nucleus accumbens module imparts risk for chronic low back pain in humans. D. In a rat model of neuropathic pain (SNI), prefrontal cortex (PFC) gray matter volume is decreased , and 5 days after SNI neuropathy NAc covariance of receptor gene expression is upregulated.

Figure 5.

Hippocampus structure and function is changed in chronic pain, over time. A. Anterior hippocampus functional connectivity is substantially upregulated in subacute, and chronic back pain patients, when compared to controls. Functional connectivity from the anterior hippocampus to the medial prefrontal cortex (right upper panel) and posterior cingulate gyrus (right bottom panel) shifts over time and differentiates patients who develop chronic pain to those who recover. B. Examining how the hippocampus changes with chronic pain reveals that hippocampal neurogenesis is substantially downregulated in SNI animals compared to sham C. Identifying these mechanisms allows to probe for new treatments. In SNI animals, direct stimulation of the dorsal hippocampus leads to changes in behavior (changes in place preference in chambers with optogenetic stimulation, left panel) and a total extinguishment of mechanical allodynia(right panel).