Chronic pain changes the brain
Researchers at the Institute for Biomedical Research and Innovation at Cádiz (INiBICA), affiliated with the University of Cádiz (UCA) and the CIBER Mental Health Network (CIBERSAM), have identified neural connections responsible for modulating pain and depressive symptoms resulting from chronic pain. The studies, led by Professor Esther Berrocoso and the late Professor Juan Antonio Micó, culminated in the publication of “Pain and depression comorbidity causes asymmetric plasticity in the locus coeruleus neurons” in the prestigious journal *Brain*.
It is well known that many patients with chronic pain are susceptible to mental health conditions, such as depression or anxiety disorders. However, the neurobiological mechanisms involved remain poorly understood, making it difficult to treat these conditions effectively. For this reason, this research group has focused on studying the biological mechanisms involved in one type of pain—neuropathic pain—whose therapeutic management remains highly complex. This pain can have various causes: it may result from nerve compression (for example, due to a tumor, a herniated disc, or carpal tunnel syndrome), or it may result from nerve damage affecting the entire body (diabetes mellitus), a specific area (pain due to shingles [herpes zoster]), or even abnormal processing of pain signals, as occurs in phantom limb pain. Researchers are focusing their studies on the locus coeruleus, the central nervous system’s primary noradrenergic nucleus, which plays a key role in pain processing and connects the spinal cord to cortical areas responsible for the sensory and emotional processing of pain.
Using innovative methodological approaches such as DREADDs (an acronym for Designer Receptors Exclusively Activated by Designer Drugs), which allow for the selective modulation of neuronal activity, researchers have demonstrated that the connections between the locus coeruleus and the spinal cord play a significant role in pain relief only at the onset of neuropathy, suggesting that endogenous analgesic function becomes depleted. Furthermore, interrupting the connection between the locus coeruleus and the anterior cingulate cortex alleviates the depressive behavior observed in animals with neuropathic pain. Similarly, a pharmacological study demonstrated the involvement of alpha-adrenergic receptors in the anterior cingulate cortex responsible for the depressive phenotype.
These results demonstrate that chronic pain causes various changes in the central nervous system over time. Thus, in the early stages of the pain process, adaptations mediated by the descending noradrenergic pathway to the spinal cord occur, reducing the pain experienced by the subject. However, when the pain process persists over time, connections from the locus coeruleus to the anterior cingulate cortex are activated, which may contribute to the onset of depression-related symptoms. In other words, norepinephrine has a beneficial analgesic effect at the spinal level but can be counterproductive in higher brain areas, causing undesirable effects. These findings may help explain why current antineuropathic drugs that promote noradrenergic activation require complementary mechanisms of action, such as the modulation of ion channels (gabapentin), serotonergic pathways (amitriptyline or duloxetine), or even opioid receptors (tapentadol and tramadol). Furthermore, this study demonstrates the importance of seeking new personalized therapeutic approaches to halt the chronic progression of pain and associated mental health conditions.
