Neuropathic pain

Peripheral neuropathic chronic pain is a severe and debilitating pathological condition which affects many millions of people. Neuropathic pain is a consequence of either neurotropic infections (most notably HIV) or injuries of peripheral nerves, which may occur following trauma, nerve compression or diabetes. The mechanisms of neuropathic pain are poorly understood and existing therapy is often ineffective. Very recently the role of glial cells, particularly microglia and to a lesser extent astroglia, as primary mediators of chronic pain, has begun to be considered and gained substantial experimental support. It is now firmly established that injury to peripheral nerve causes rapid and significant activation of microglia in the dorsal horn of the spinal cord on the side of the peripheral nerve entry (Figure 10.8). The activated microglial cells in spinal cord express pain related signalling molecules - P2X4 purinoreceptors and p38 mitogen-activated protein kinase (p38 MAPK). The activation of P2X4 receptors is necessary and sufficient to produce allodynia (pain arising from stimuli which are normally not painful), which is a very common symptom of chronic pain. Direct injection of P2X4 stimulated microglia into rat spinal cord triggers allodynia; conversely, pharmacological inhibition of P2X4 receptors reverses allodynia following experimental peripheral nerve injury. Similarly important is microglial p38 MAPK, which is rapidly activated following nerve injury, and pharmacological inhibition

Schwan Cells

Normal side ! Injury side

Figure 10.8 Activation of microglia as a mediator of neuropathic pain. Injury of peripheral nerves triggers activation of microglia in the ipsilateral side of the dorsal horn. This activation is mediated through P2X4 ionotropic purinoreceptors and contributes to the development of chronic pain. (Modified from Tsuda M, Inoue K, Salter MW (2005) Neuropathic pain and spinal microglia: a big problem from molecules in 'small' glia. Trends Neurosci 28, 101-107)

Normal side ! Injury side

Figure 10.8 Activation of microglia as a mediator of neuropathic pain. Injury of peripheral nerves triggers activation of microglia in the ipsilateral side of the dorsal horn. This activation is mediated through P2X4 ionotropic purinoreceptors and contributes to the development of chronic pain. (Modified from Tsuda M, Inoue K, Salter MW (2005) Neuropathic pain and spinal microglia: a big problem from molecules in 'small' glia. Trends Neurosci 28, 101-107)

of p38 MAPK attenuates neuropathic pain symptoms. How microglia affect spinal cord sensory neurones and increase their excitability (which in turn underlies the enhanced firing discharges of these neurones and produces the sensation of pathological pain) remains unknown; it could be mediated by various neuroac-tive substances (such as ATP or proinflammatory cytokines) released by activated microglia, acting directly or as intermediate signals.

Spinal cord astrocytes also demonstrate signs of reactive gliosis following peripheral nerve injury. These astrocytes express some receptors related to pain; most notably vanilloid receptors type 1 (also known as capsaicin receptors; activated by obnoxious heat and chilli pepper) and cannabinoid receptors type 1. Peripheral nerve injury increases the synthesis of growth factors (e.g. FGF2) and cytokines in astroglial cells in the spinal cord. The precise role played by astrocytes in chronic pain remains to be uncovered.

Peripheral Neuropathy Natural Treatment Options

Peripheral Neuropathy Natural Treatment Options

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