Neuroimmune Activation and Neuroinflammation in Chronic Pain and Opioid Tolerance/Hyperalgesia

Abstract

One area that has emerged as a promising therapeutic target for the treatment and prevention of chronic pain and opioid tolerance/hyperalgesia is the modulation of the central nervous system (CNS) immunological response that ensues following injury or opioid administration. Broadly defined, central neuroimmune activation involves the activation of cells that interface with the peripheral nervous system and blood. Activation of these cells, as well as parenchymal microglia and astrocytes by injury, opioids, and other stressors, leads to subsequent production of cytokines, cellular adhesion molecules, chemokines, and the expression of surface antigens that enhance a CNS immune cascade. This response can lead to the production of numerous pain mediators that can sensitize and lower the threshold of neuronal firing: the pathologic correlate to central sensitization and chronic pain states. CNS innate immunity and Toll-like receptors, in particular, may be vital players in this orchestrated immune response and may hold the answers to what initiates this complex cascade. The challenge remains in the careful perturbation of injury/opioid-induced neuroimmune activation to down-regulate this process without inhibiting beneficial CNS autoimmunity that subserves neuronal protection following injury.

CNS‐infiltrating CD4+ T lymphocytes contribute to murine spinal nerve transection‐induced neuropathic pain

“…Iba-1 or MHC class II expression. The observed differential immunoreactivity in GFAP between WT and CD4 KO mice is consistent with the concept that astrocytes have been associated with the maintenance of L5Tx-induced neuropathic pain [3]. Our previous observations of increases in the costimulatory molecule B7.2 and MHC class II in the lumbar spinal cord post L5Tx and significantly decreased pain behaviors post L5Tx in MHC class II KO mice [4,6,7] support the involvement of T lymphocyte-mediated adaptive immunity in pain.…”

“…It has been shown that glial activation post L5Tx plays a key role in L5Tx-induced behavioral hypersensitivity [3]. Therefore, we examined astrocytic and microglial responses at day 7 post L5Tx in both WT and CD4 KO mice via immunohistochemistry.…”

“…Towards this end, many rodent models of neuropathy have been developed and utilized to decipher central and peripheral nervous system mechanisms that give rise to long-lasting behavioral hypersensitivity, the animal correlate of painful neuropathy in humans [2]. A novel mechanistic theme has emerged in the last decade implicating a role of central nervous system (CNS) innate and adaptive immunity in both the generation and maintenance of chronic pain syndromes [3].…”

Possible role of spinal astrocytes in maintaining chronic pain sensitization: review of current evidence with focus on bFGF/JNK pathway

“…Because inhibition of JNK suppresses SNL-induced phosphorylation of c-Jun in spinal astrocytes (Zhuang et al, 2006a), JNK activation is likely to regulate gene transcription in spinal astrocytes via activation of the transcription factor c-Jun and other transcription factors such as ATF-2. After nerve injury, there is increased synthesis in the spinal cord of inflammatory mediators such as cytokines , nitric oxide (NO), which is produced by inducible NO synthase (iNOS), and prostaglandin E2 (PGE2) (produced by either COX-1 or COX-2); all these mediators and enzymes are implicated in pain sensitization (Samad et al, 2001;Watkins et al, 2001;DeLeo et al, 2004;Ji and Strichartz, 2004). Mixed lineage kinases (MLK) are specific JNK kinases.…”

“…CD11b, TLR4 and CD14) within several hours . Initially, microglia appear to be activated, which activates astrocytes (Aldskogius and Kozlova, 1998;DeLeo et al, 2004). Specifically, nerve injury upregulates several receptors, such as the chemokine receptor CX3CR1 and ATP receptor P2X4 in spinal microglia.…”