Abstract
More than a decade ago the novel concept that glial cells are major players in the modulation of pain mechanisms in the spinal cord has started a prolific series of work addressing the modalities of neuron-glia communication. Mike Salter with Kazuhide Inoue laboratories introduced ATP as pivotal mediator for such communication via activation of P2X4 receptors expressed by microglia in the dorsal horn ipsilateral to a peripheral nerve injury. Activation of P2X4 receptors result in release of the neurotrophin BDNF, which, through the activation of neuronal TrkB receptors, alters neuronal excitability and this effect is associated with behavioural ipsilateral allodynia. This viewpoint article compares the evidence supporting a biological relevance of the P2X4 and BDNF system in neuropathic pain with recent data which question such importance. Having read this article, readers will be able to formulate their own opinion on such controversy.
Highlights
More than a decade ago the seminal work of Linda Watkins and Joyce DeLeo groups started a novel line of research in the pain field, promoting the novel concept that glial cells are major players in the modulation of pain mechanisms in the spinal cord (Watkins and Maier, 2003; DeLeo and Yezierski, 2001)
Evidence from Salters’ and Inoue’s laboratories indicates that following peripheral nerve injury, microglia in the ipsilateral dorsal horn of the spinal cord, de novo express P2X4 receptors via increased expression of interferon regulatory factor 8 (IRF8) and IRF5 which bind to the promoter region of the p2x4 gene (Tsuda et al, 2003; Coull et al, 2005; Tsuda, 2016)
Single nucleotide polymorphisms (SNPs) in the p2x7 gene that are known cause gain-of pain-function and loss of-pain-function result in changes in i) pore and protein levels in recombinant cell studies and ii) pain sensitivity in diabetic patients (Ursu et al, 2014). This view point has laid out some of the current evidence in favour and against the microglial P2X4-brain-derived neurotrophic factor (BDNF) pathway playing a significant role in neuropathic pain with the aim to provide an unbiased opinion
Summary
More than a decade ago the seminal work of Linda Watkins and Joyce DeLeo groups started a novel line of research in the pain field, promoting the novel concept that glial cells are major players in the modulation of pain mechanisms in the spinal cord (Watkins and Maier, 2003; DeLeo and Yezierski, 2001). Activation of this receptor results in release of the neurotrophin BDNF, which, through the activation of neuronal TrkB receptors, alters neuronal excitability and this effect is associated with behavioural hyperalgesia and allodynia under neuropathic conditions. We suggested that certain noxious stimuli that produce bursting activity in nociceptive fibres, result in the release of BDNF, which binds TrkB receptors that are discretely expressed by dorsal horn neurons (Mannion et al, 1999; Salio et al, 2005).
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