How do opioids control pain circuits in the brainstem during opioid-induced disorders and in chronic pain? Implications for the treatment of chronic pain

Abstract

Brainstem areas involved in descending pain modulation are crucial for the analgesic actions of opioids. However, the role of opioids in these areas during tolerance, opioid-induced hyperalgesia (OIH), and in chronic pain settings remains underappreciated. We conducted a revision of the recent studies performed in the main brainstem areas devoted to descending pain modulation with a special focus on the medullary dorsal reticular nucleus (DRt), as a distinctive pain facilitatory area and a key player in the diffuse noxious inhibitory control paradigm. We show that maladaptive processes within the signaling of the µ-opioid receptor (MOR), which entail desensitization and a switch to excitatory signaling, occur in the brainstem, contributing to tolerance and OIH. In the context of chronic pain, the alterations found are complex and depend on the area and model of chronic pain. For example, the downregulation of MOR and δ-opioid receptor (DOR) in some areas, including the DRt, during neuropathic pain likely contributes to the inefficacy of opioids. However, the upregulation of MOR and DOR, at the rostral ventromedial medulla, in inflammatory pain models, suggests therapeutic avenues to explore. Mechanistically, the rationale for the diversity and complexity of alterations in the brainstem is likely provided by the alternative splicing of opioid receptors and the heteromerization of MOR. In conclusion, this review emphasizes how important it is to consider the effects of opioids at these circuits when using opioids for the treatment of chronic pain and for the development of safer and effective opioids.

Degree centrality-based resting-state functional magnetic resonance imaging explores central mechanisms in lumbar disc herniation patients with chronic low back pain

“…The brainstem, a fundamental component of the central nervous system, oversees numerous vital physiological functions and neuromodulatory processes. It comprises regions capable of processing incremental nociceptive information and modulating neurotransmission at primary nociceptive synapses, both directly and indirectly ( 35 , 36 ). Preclinical and human studies on brainstem pain modulatory circuits have elucidated the pain-modulatory functions of several key brainstem structures ( 2 , 37 , 38 ).…”