Pathological and protective roles of glia in chronic pain

Abstract

Glia have emerged as key contributors to pathological and chronic pain mechanisms. On activation, both astrocytes and microglia respond to and release a number of signalling molecules, which have protective and/or pathological functions. Here we review the current understanding of the contribution of glia to pathological pain and neuroprotection, and how the protective, antiinflammatory actions of glia are being harnessed to develop new drug targets for neuropathic pain control. Given the prevalence of chronic pain and the partial efficacy of current drugs, which exclusively target neuronal mechanisms, new strategies to manipulate neuron-glia interactions in pain processing hold considerable promise.Under normal conditions, in otherwise healthy subjects, acute-pain processing consists of a chain of events that begins with stimuli that activate specialized receptive endings on peripheral sensory nerve fibres. Following such activation, excitatory impulses carried by the sensory afferent axons induce excitatory postsynaptic potentials in pain-transmission neurons located in the dorsal horn of the spinal cord, with the final synaptic relay occurring in the cortex. However, pain processing is not simply a relay of signals from the body to the brain, it is a redundant, multi-pathway and dynamic system in which profound pain suppression or enhancement can occur at any level of synaptic communication. When dysfunctional pain signalling (for example, pain signalling in the absence of tissue damage) occurs, pathological pain ensues. Lesions of the nervous system can produce a form of pathological pain, neuropathic pain, which is characterized by unexplainable widespread pain, a sensory deficit, a burning sensation, pain caused by light touch (allodynia), or acute pain in the absence of a noxious stimulus 1 . Furthermore, chronic neuropathic pain can persist for months, without the underlying cause being treatable or identifiable.Our understanding of pathological pain has primarily revolved around neuronal mechanisms. However, neighbouring astrocytes and microglia have recently been recognized as powerful modulators of pain and are emerging as a new target for drug development. Although glia are well known for having a number of housekeeping functions that are necessary for healthy neuronal communication, on strong activation they act as immunoresponsive cells or exert a neuroprotective effect. Glia can contribute to neuropathic-pain processing by releasing a number of glial and neuronal signalling molecules. These include, among others, the classic immune signals: cytokines and chemokines. There is substantial evidence that both astrocyte and microglia activation lead to pro-inflammatory responses with pathological effects, such as neuronal hyperexcitability, neurotoxicity and chronic inflammation. However, the notion that

Posttraumatic stress disorder influences the nociceptive and intrathecal cytokine response to a painful stimulus in combat veterans

“…Besides signs of neuroinflammation as reflected by CSF cytokine indices, brain positron emission tomography (PET) scans of patients with chronic back pain show microglial cell specific activation (greater than healthy controls) in: 1) medial thalamic, 2) post central gyrus, and 3) paracentral lobule, suggesting that chronic pain mediated neuroinflammation and central sensitization likely co-occur in both the brain and spinal cord (Loggia et al, 2015). The mechanisms of central sensitization are known to involve neuronal interaction with activated glia cells and astrocytes (Milligan and Watkins, 2009;Watkins and Maier, 2005). Activated microglia and astrocytes release pro-inflammatory cytokines/chemokines such as TNF␣, IL-1␤, IL-6 and IL-8, in addition to glutamate and substance P, which collectively are known to amplify pain (Milligan and Watkins, 2009;Watkins and Maier, 2005).…”

“…The mechanisms of central sensitization are known to involve neuronal interaction with activated glia cells and astrocytes (Milligan and Watkins, 2009;Watkins and Maier, 2005). Activated microglia and astrocytes release pro-inflammatory cytokines/chemokines such as TNF␣, IL-1␤, IL-6 and IL-8, in addition to glutamate and substance P, which collectively are known to amplify pain (Milligan and Watkins, 2009;Watkins and Maier, 2005).…”

Evaluating the role of Toll-like receptors in diseases of the central nervous system

“…This type of pain in not protective and is itself regarded as a pathological condition [82]. In contrast to inflammatory pain, treatments for neuropathic pain is lacking, and therefore is a requirement to understand its molecular pathogenesis [83].…”

“…The use of animal models of neuropathic pain reveal activation of microglia and astrocytes in the spinal cord and the production of IL-1β and TNFα which are important in the initiation and maintenance of neuropathic pain [82].…”

“…Intriguingly it has been demonstrated that opioids activate microglia via TLR4 and morphine induces TLR4 signalling in HEK 293 cells [82]. Opioid activation of microglia via TLR4 produces undesirable effects such as a reduction of opioid analgesia and increases opioid tolerance, dependence, reward and respiratory depression [88].…”