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Review
. 2016 Sep 13;6(9):e888.
doi: 10.1038/tp.2016.168.

Glial contributions to visceral pain: implications for disease etiology and the female predominance of persistent pain

K N Dodds  1 , E A H Beckett  1 , S F Evans  2   3 , P M Grace  2   4 , L R Watkins  4 , M R Hutchinson  1   5
Affiliations
Review

Glial contributions to visceral pain: implications for disease etiology and the female predominance of persistent pain

K N Dodds et al. Transl Psychiatry. .

Abstract

In the central nervous system, bidirectional signaling between glial cells and neurons ('neuroimmune communication') facilitates the development of persistent pain. Spinal glia can contribute to heightened pain states by a prolonged release of neurokine signals that sensitize adjacent centrally projecting neurons. Although many persistent pain conditions are disproportionately common in females, whether specific neuroimmune mechanisms lead to this increased susceptibility remains unclear. This review summarizes the major known contributions of glia and neuroimmune interactions in pain, which has been determined principally in male rodents and in the context of somatic pain conditions. It is then postulated that studying neuroimmune interactions involved in pain attributed to visceral diseases common to females may offer a more suitable avenue for investigating unique mechanisms involved in female pain. Further, we discuss the potential for primed spinal glia and subsequent neurogenic inflammation as a contributing factor in the development of peripheral inflammation, therefore, representing a predisposing factor for females in developing a high percentage of such persistent pain conditions.

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Figures

Figure 1
Figure 1
Schematic representation of the major proinflammatory glial-mediated alterations to excitatory synapses within the spinal dorsal horn that contribute to central sensitization. Strong or long-term noxious activation of astrocytes and microglia within the spinal dorsal horn can lead to the aberrant synthesis and release of proinflammatory mediators, such as TNFα and IL-1β. The overarching effect of these neurokine signals in excitatory synapses contributes to central sensitization and facilitates the transmission of nociceptive signals to the brain. Some of the major known adaptations include the following. (1) Increased release of the excitatory neurotransmitter, glutamate, from presynaptic nerve terminals. (2) Suppression of astrocytic glutamate reuptake via downregulation of GLT-1 and GLAST activity. (3) Release of the glutamate from astrocytes, which is capable of increasing the excitability of nearby neurons. (4) d-serine, also released from astrocytes, enhances Ca2+ influx via binding to glycine sites on NMDA receptors on postsynaptic neurons. (5) Astrocytic release of ATP also increases postsynaptic excitability via activation of ligand-gated purinergic receptors, P2X4R and P2X7R. (6) TNFα and IL-1β increase translocation of NMDA receptors to the postsynaptic membrane and increases their conductance via an ERK-dependent pathway. (7) IL-1β, TNFα, IFNγ and CCL2 increase NMDA receptor-mediated excitatory signaling; in the case of IL-1β, this is thought to involve the phosphorylation of receptor subunits including NR1, 2a and 2b. (8) Proinflammatory cytokines have been linked to increased expression and activation of AMPA receptors at excitatory synapses. (9) Reactive microglia have increased expression of receptors for various neurotransmitters and chemokines (for example, AMPARs, NK1Rs and CX3CR1), which can induce the further release of proinflammatory cytokines upon stimulation, thereby perpetuating neuronal excitation. ERK, extracellular signal-regulated kinase; IFN, interferon; IL, interleukin; TNFα, tumor necrosis factor-α.
Figure 2
Figure 2
Schematic depicting the major proinflammatory glial-mediated changes to inhibitory synapses within the spinal dorsal horn that facilitate central sensitization. As mentioned in Figure 1, prolonged stimulation of astrocytes and microglia can lead to the increased synthesis and release of various proinflammatory cytokines and chemokines. Within inhibitory synapses of the spinal cord dorsal horn, the effects of these mediators ultimately lead to a reduction in inhibitory neurotransmission (‘disinhibition'), which further facilitates central sensitization. For example: (1) IL-1β can mediate a decrease in the astrocytic uptake of glutamate, via a PKC-mediated suppression of glutamate transporter GLT-1. (2) The reduced uptake of glutamate via GLT-1 leads to decreased availability of glutamine for GABA synthesis. (3) IL-1β and IL-6 inhibit presynaptic GABA and glycine currents. (4) Last, IL-1β, PGE2, CCL2, TNFα and IFNγ decrease GABA and glycine receptor activity; in the case of IL-1β, this is thought to be mediated via a PKC-dependent pathway. IFN, interferon; IL, interleukin; PKC, protein kinase C; TNFα, tumor necrosis factor-α.
Figure 3
Figure 3
Possible involvement of centrally mediated neurogenic inflammation in the development of visceral inflammatory disease in the periphery: example for endometriosis. (1) During menstruation, endometrial debris passes both per vaginum and in a retrograde fashion through the fallopian tubes to the peritoneal cavity. (2) In certain women, the inflammatory events initiated by ectopic endometrial tissue activate sensory afferents innervating adjacent visceral structures, which transmit the noxious information to the spinal dorsal horn. In addition to exciting ascending neural signals projecting to the brain, afferent neurotransmitter release could potentially also activate spinal astrocytes and microglia, whose proinflammatory products contribute to the development of central sensitization and exaggerated pain (see Figures 1 and 2 for details). (3) Strong ongoing afferent stimulation associated with regular monthly menstruation and dysmenorrhea, as well as the excitatory environment created by reactive glia, may reciprocally activate the central terminals of sensory nerves. This can then induce the antidromic release of neuropeptides (such as SP and CGRP) at the peripheral site of disease (the ‘dorsal root reflex'). (4) The subsequent induction of neurogenic inflammation, including the release of cytokines (IL-1β and TNFα), PGE2 and nerve growth factor (NGF) from local immune cells, may then contribute to an environment that encourages the implantation of endometrial debris onto the peritoneum, and the development of endometriotic lesions (including the associated neovascularization and sprouted innervation). CGRP, calcitonin gene-related peptide; IL, interleukin; PGE2, prostaglandin E2; TNFα, tumor necrosis factor-α.
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