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Review
, 66 (1), 80-101

Neuroinflammation and Comorbidity of Pain and Depression

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Review

Neuroinflammation and Comorbidity of Pain and Depression

A K Walker et al. Pharmacol Rev.

Abstract

Comorbid depression and chronic pain are highly prevalent in individuals suffering from physical illness. Here, we critically examine the possibility that inflammation is the common mediator of this comorbidity, and we explore the implications of this hypothesis. Inflammation signals the brain to induce sickness responses that include increased pain and negative affect. This is a typical and adaptive response to acute inflammation. However, chronic inflammation induces a transition from these typical sickness behaviors into depression and chronic pain. Several mechanisms can account for the high comorbidity of pain and depression that stem from the precipitating inflammation in physically ill patients. These mechanisms include direct effects of cytokines on the neuronal environment or indirect effects via downregulation of G protein-coupled receptor kinase 2, activation of the tryptophan-degrading enzyme indoleamine 2,3-dioxygenase that generates neurotropic kynurenine metabolites, increased brain extracellular glutamate, and the switch of GABAergic neurotransmission from inhibition to excitation. Despite the existence of many neuroimmune candidate mechanisms for the co-occurrence of depression and chronic pain, little work has been devoted so far to critically assess their mediating role in these comorbid symptoms. Understanding neuroimmune mechanisms that underlie depression and pain comorbidity may yield effective pharmaceutical targets that can treat both conditions simultaneously beyond traditional antidepressants and analgesics.

Figures

Fig. 1.
Fig. 1.
Timing and overlap of sickness and acute pain with depression and chronic pain. Sickness during acute inflammation represents an adaptive response to infection or tissue damage. These acute symptoms include enhanced pain sensitivity, neurovegetative symptoms (e.g., fatigue, reduced appetite, sleep disorders), and malaise, among others. However, intense chronic inflammation can lead to a transition from these adaptive normal responses to inflammation to chronic conditions of depression and chronic pain that can remain even after the inflammation has subsided. During the period of typical sickness behavior, the evidence suggests that the pain and depressive phenomena are reversible. However, if the transition to depression and chronic pain has already taken place, then it may be too late for intervention using drugs that target merely sickness and acute pain.
Fig. 2.
Fig. 2.
PAMPs and DAMPs trigger the inflammatory response to infection and tissue damage. Tissue damage can often lead to infection and vice versa, thus the activation of DAMPs and PAMPs usually co-occur. These in turn activate pattern recognition receptors such as TLRs, which induce the transcription of proinflammatory cytokines by factors such as NF-κB and MAPKs, which can then promote the further transcription of cytokines. IL-1β is produced in response to PAMPs via NOD-like receptors (NLRs), which ultimately activate caspase-1, resulting in the cleavage of Pro-IL-1β to mature IL-1β.
Fig. 3.
Fig. 3.
Immune-to-brain signaling pathways. Once PAMPs and DAMPs trigger the production of the inflammatory response, inflammatory signals need to reach the brain to induce sickness responses and behaviors. Cytokines can bypass the BBB via circumventricular organs (CVOs), or are transported across the BBB by specific transport mechanisms. Afferent vagal nerves can send the cytokine signal from peripheral tissue to the base of the brain. Adapted from Quan (2008) with permission from Springer Science and Business Media.
Fig. 4.
Fig. 4.
The transition from acute to chronic pain in GRK2-deficient mice. Acute inflammation in mice with normal GRK2 levels results in the typical response and duration of microglial activation, with the ability to readily and quickly attenuate the inflammatory response. Thus, these mice experience hyperalgesia transiently. In mice with low microglial/macrophage GRK2 levels, the response and duration of microglial activation is extended, decreasing the expediency of attenuating the inflammatory response. Thus, these mice experience longer durations of hyperalgesia. Note that low GRK2 mice have not yet been tested in models of neuropathic pain. However, it is known that GRK2 is reduced in microglia in models of neuropathic pain.
Fig. 5.
Fig. 5.
Kynurenine pathway of tryptophan metabolism in response to inflammation. Tryptophan is metabolized intracellularly by IDO and TDO to produce kynurenine. In response to inflammation, there is an increase in the metabolism of kynurenine down the kynurenine monooxygenase (KMO) pathways, which results in increased production of quinolinic acid, which agonizes NMDA receptors (NMDA-R). 3-HK, 3-hydroxy kynurenine; KATs, kynurenine aminotransferases.

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