3 research outputs found

    Long-term potentiation in spinal nociceptive pathways as a novel target for pain therapy

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    Long-term potentiation (LTP) in nociceptive spinal pathways shares several features with hyperalgesia and has been proposed to be a cellular mechanism of pain amplification in acute and chronic pain states. Spinal LTP is typically induced by noxious input and has therefore been hypothesized to contribute to acute postoperative pain and to forms of chronic pain that develop from an initial painful event, peripheral inflammation or neuropathy. Under this assumption, preventing LTP induction may help to prevent the development of exaggerated postoperative pain and reversing established LTP may help to treat patients who have an LTP component to their chronic pain. Spinal LTP is also induced by abrupt opioid withdrawal, making it a possible mechanism of some forms of opioid-induced hyperalgesia. Here, we give an overview of targets for preventing LTP induction and modifying established LTP as identified in animal studies. We discuss which of the various symptoms of human experimental and clinical pain may be manifestations of spinal LTP, review the pharmacology of these possible human LTP manifestations and compare it to the pharmacology of spinal LTP in rodents

    Novel intracellular mechanisms of NMDA receptor-dependent spinal nociceptive plasticity

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    Prolonged activation of spinal NMDA receptors, after peripheral inflammation or nerve damage, can activate intracellular signalling cascades leading to plastic changes in synaptic transmission. This results in central sensitization of dorsal horn sensory neurones and manifests in patients as increased sensitivity to painful stimuli (hyperalgesia), and pain resulting from normally non-painful tactile stimuli (allodynia). Therefore, targeting NMDA-mediated intracellular signalling pathways could be a successful analgesic strategy, potentially devoid of side-effects associated with receptor blockade. NMDA receptors bind to the intracellular scaffold protein PSD-95, which couples the receptor to cytoplasmic effector pathways. The role of this coupling in spinal sensory transmission and nociceptive plasticity was investigated using biochemical, electrophysiological and behavioural methods. Disruption of binding between PSD-95 and NR2B subunits of NMDA receptors was achieved through the use of a decoy mimetic peptide, Tat-NR2B9c. I show that Tat-NR2B9c selectively reduces wind-up of dorsal horn wide dynamic range neurones and prevents both neuronal and behavioural measures of formalin-induced central sensitization. In the spinal nerve ligation model of chronic pain, Tat-NR2B9c reduced neuronal responses to mechanical and thermal stimulation and was able to reverse behavioural mechanical and cold hypersensitivity, clinical signs of neuropathic pain. In addition, the roles of two kinases, atypical PKCζ/PKMζ and PI3K, known to be involved in hippocampal LTP, were investigated using biochemical, immunohistochemical, electrophysiological and behavioural measures. I found that activation of spinal PKCζ/PKMζ is dependent on coupling between NR2B-subtype receptors and PSD-95, and contributes to central sensitization of dorsal horn neurones. PI3K was also found to be active in the NMDA-dependent formalin model and regulates various intracellular mechanisms in central sensitization. Finally, I investigated the role of DDAH-1, an enzyme which is involved in the regulation of nNOS, in spinal nociceptive plasticity. DDAH-1 inhibition reduced neuronal wind-up and both neuronal and behavioural measures of formalin-induced central sensitization. These findings further our understanding of NMDA-dependent spinal nociceptive plasticity. Disrupting the interaction between NR2B-containing NMDA receptors and PSD-95 or inhibition of downstream intracellular signalling pathways may be successful analgesic strategies for the treatment of chronic pain
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