Neuroimmune Interactions in Pain and Stress: An Interdisciplinary Approach

Abstract

Mounting evidence indicates that disruptions in bidirectional communication pathways between the central nervous system (CNS) and peripheral immune system underlie the etiology of pathologic pain conditions. The purpose of this review is to focus on the cross-talk between these two systems in mediating nociceptive circuitry under various conditions, including nervous system disorders. Elevated and prolonged proinflammatory signaling in the CNS is argued to play a role in psychiatric illnesses and chronic pain states. Here we review current research on the dynamic interplay between altered nociceptive mechanisms, both peripheral and central, and physiological and behavioral changes associated with CNS disorders.

Keywords: neuroimmunology; pain; stress.

Figure 1.

Pain is a complex experience involving sensory-discriminative, affective-motivational, and cognitive-evaluative dimensions. The experience of pain and responses to pain result from interactions of biological, psychological, and social factors. The interactions among these pathways are complex and reciprocal. Emerging evidence suggests that neuroinflammation in the peripheral and central nervous systems plays a critical role in the onset and progression of pain. Inflammation signals the brain to induce sickness responses that include increased pain and negative affect. Therefore, immune activation and inflammation play a critical role in the cross-talk between the central nervous system and peripheral immune system during states of stress, psychiatric illness, and abnormal pain conditions. Understanding neuroimmune mechanisms that underlie pain and comorbid symptoms may yield novel therapeutic strategies that integrate a collaborative and interdisciplinary approach in the treatment of chronic pain.

Figure 2.

Interpretation of psychological stress in the brain activates neuroendocrine pathways that signal into the periphery, including the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS). HPA activation leads to the release of circulating corticosterone/cortisol (CORT) that promotes trafficking of monocytes from the bone marrow, which feedback to the brain to influence behavior. Activation of the SNS leads to increased release of epinephrine (EPI) in circulation, which primes the monocytic response to future activation. CORT provides negative feedback at multiple levels of HPA regulation and inhibits central noradrenergic release (dashed lines indicate negative feedback). Another critical element of HPA and SNS activation is that these signals are relayed to the immune system. Therefore, a major component of the stress response involves relaying information from the brain to peripheral organs and the immune system via HPA and SNS neuroendocrine pathways.

Figure 3.

The experience of pain depends on efficient transmission of nociceptive information from peripheral nociceptor neurons to second order interneurons in the spinal cord, and then onto supraspinal structures. First-order primary afferent neurons transmit nociceptive signals from a peripheral stimulus site to the spinal cord via the dorsal root ganglion and synapse with second-order nociceptive projection neurons in the spinal dorsal horn. Secondary order projection neurons ascend in the contralateral spinothalamic and spinoreticular tracts that relay the signal to cortical centers. Descending pathways projecting from the periaqueductal gray (PAG) in the midbrain and the rostral ventromedial medulla (RVM) to the dorsal horn influence pain transmission.

Figure 4.

(A) In the dorsal horn, incoming afferent pain signals cause the release of neurotransmitters that bind to and activate postsynaptic receptors on pain transmission neurons. Microglia are present but quiescent, actively surveying the neuronal environment and responding to minute homeostatic disturbances. As a protective mechanism, microglia produce proinflammatory cytokines and chemokines to support endangered neurons. (B) With repeated social defeat (RSD) stress, incoming afferent signals are increased, and presynaptic release of neurotransmitters is enhanced. Microglia become further activated and increase production of proinflammatory cytokines/immune mediators and chemokines that further increase presynaptic release and postsynaptic hyperexcitability.

Figure 5.

Pharmacological ablation of microglia with colony-stimulating factor 1 receptor antagonist PLX5622 allows for investigation of the role of microglia in the development of pain by stress. Mice were provided ad libitum diets of PLX5622 (PLX) or vehicle (Veh) chow for 14 days. (A, B) Following 14 days of treatment with PLX5622, microglia were eliminated from the spinal cord based on Iba-1 labeling for microglial activation. (C–E) The gene expression of microglia-related CX₃CR1 was reduced by PLX5622 throughout the spinal cord in mice exposed to repeated social defeat (RSD; Stress) and those left undisturbed as controls. Modified from Sawicki and others (2019).

Figure 6.

Microglia facilitate the transmission of pain to the brain through an inflammatory-driven mechanism. Mice were provided ad libitum diets of PLX5622 (PLX) or vehicle (Veh) chow for 14 days and then exposed to repeated social defeat (RSD; Stress) or left undisturbed as controls. (A) Mice were tested for mechanical allodynia before exposure to RSD and 12 hours after the first, third, and sixth day of stress. Before stress, each of the four treatment groups had comparable baseline withdrawal thresholds of mechanical stimulation to the hindpaw using the von Frey behavior test. Microglial depletion by PLX5622 prevented RSD-induced allodynia after three and six days of RSD. (B–D) The gene expression of critical inflammatory markers involved in nociceptive signaling were increased in the spinal cord with RSD, and induction of these genes was attenuated by microglial elimination with PLX5622. Modified from Sawicki and others (2019).