Abstract
Neuropathic pain is a common health problem that affects millions of people worldwide. Despite being studied extensively, the cellular and molecular events underlying the central immunomodulation and the pathophysiology of neuropathic pain is still controversial. The idea that 'glial cells are merely housekeepers' is incorrect and with respect to initiation and maintenance of neuropathic pain, microglia and astrocytes have important roles to play. Glial cells differentially express opioid receptors and are thought to be functionally modulated by the activation of these receptors. In this review, we discuss evidence for glia-opioid modulation of pain by focusing on the pattern of astrocyte and microglial activation throughout the progress of nerve injury/neuropathic pain. Activation of astrocytes and microglia is a key step in central immunomodulation in terms of releasing pro-inflammatory markers and propagation of a 'central immune response'. Inhibition of astrocytes before and after induction of neuropathic pain has been found to prevent and reverse neuropathic pain, respectively. Moreover, microglial inhibitors have been found to prevent (but not to reverse) neuropathic pain. As they are expressed by glia, opioid receptors are expected to have a role to play in neuropathic pain.
Highlights
With the central nervous system (CNS) no longer deemed as a passive immuneprivileged structure, it is recognised that the CNS can mount innate immune responses, which when chronically activated potentially direct the pathophysiology of a number of neurodegenerative disorders as well as having a central role to play in the development of pathological pain states and opioid drug tolerance
Such innate immunity is an inflammatory response induced by the detection of immunological proteins, released from microorganisms, and initially this occurs in structures of the brain lacking the normal blood brain barrier (BBB), such as the circumventricular organs (CVO) of the brain
M1 microglia are characterised by a high level of pro-inflammatory cytokines while the late M2 phenotype is characterised by the production of anti-inflammatory molecules such as interlukin-1 (IL-1) and transforming growth factor 1β (TGFβ) (Kumar and Loane, 2012, Chhor et al, 2013)
Summary
The idea that ‘glial cells are merely housekeepers’ is incorrect and with respect to initiation and maintenance of neuropathic pain microglia and astrocytes have important roles to play. We introduce evidence for glia-opioid modulation of pain by focusing on the pattern of astrocyte and microglial activation throughout the progress of nerve injury/neuropathic pain. Inhibition of astrocytes before and after induction of neuropathic pain has been found to prevent and reverse neuropathic pain, respectively. Microglial inhibitors have been found to prevent (but not to reverse) neuropathic pain. As they are expressed by glia, opioid receptors are expected to have a role to play in the treatment of neuropathic pain
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