The role of neuroinflammation in the transition of acute to chronic pain and the opioid-induced hyperalgesia and tolerance

Abstract

Current evidence suggests that activation of glial and immune cells leads to increased production of proinflammatory mediators, creating a neuroinflammatory state. Neuroinflammation has been proven to be a fundamental mechanism in the genesis of acute pain and its transition to neuropathic and chronic pain. A noxious event that stimulates peripheral afferent nerve fibers may also activate pronociceptive receptors situated at the dorsal root ganglion and dorsal horn of the spinal cord, as well as peripheral glial cells, setting off the so-called peripheral sensitization and spreading neuroinflammation to the brain. Once activated, microglia produce cytokines, chemokines, and neuropeptides that can increase the sensitivity and firing properties of second-order neurons, upregulating the signaling of nociceptive information to the cerebral cortex. This process, known as central sensitization, is crucial for chronification of acute pain. Immune-neuronal interactions are also implicated in the lesser-known complex regulatory relationship between pain and opioids. Current evidence suggests that activated immune and glial cells can alter neuronal function, induce, and maintain pathological pain, and disrupt the analgesic effects of opioid drugs by contributing to the development of tolerance and dependence, even causing paradoxical hyperalgesia. Such alterations may occur when the neuronal environment is impacted by trauma, inflammation, and immune-derived molecules, or when opioids induce proinflammatory glial activation. Hence, understanding these intricate interactions may help in managing pain signaling and opioid efficacy beyond the classical pharmacological approach.

αO-Conotoxin GeXIVA[1,2] Reduced Neuropathic Pain and Changed Gene Expression in Chronic Oxaliplatin-Induced Neuropathy Mice Model

“…Firstly, the spinal cord plays a vital role in pain signal transmission, and the L4-L6 section is commonly used in neuropathic pain related to nerve injury or CIPN studies [28,29]. The transition from acute to chronic pain involves central neuroinflammation mechanisms like glial activation [30], and we used a chronic oxaliplatin-induced CIPN model in this research. Secondly, previous RgIA results showed that the peripherally acting α9α10 nAChR antagonist could affect CNS glial cells [16].…”

Extended Treatment with Micron-Size Oral Palmitoylethanolamide (PEA) in Chronic Pain: A Systematic Review and Meta-Analysis

“…From a pathophysiological point of view, the benefits of an extended treatment with oral micron-size PEA in chronic pain may be explained by considering the specific role of the neuroinflammation in promoting and maintaining pain in different conditions. It is well known that neuroinflammation plays a key role in the onset and evolution of chronic pain and probably also in the transition from acute to chronic pain [ 64 ]. In fact, the so-called “non-neuronal cells” (microglia and mast cells) are considered the main responsible actors of this process [ 10 ].…”

New Insight into Neuropathic Pain: The Relationship between α7nAChR, Ferroptosis, and Neuroinflammation

“…Neuroinflammation is characterized by an inflammatory response occurring within the central nervous system (CNS) as a result of both exogenous and endogenous factors [ 20 ]. It is an inflammatory cascade reaction involving various immune cells and/or molecules [ 21 ].…”