Current opinion in pharmacology
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Curr Opin Pharmacol · Feb 2012
ReviewHyperalgesia by synaptic long-term potentiation (LTP): an update.
Long-term potentiation of synaptic strength (LTP) in nociceptive pathways shares principle features with hyperalgesia including induction protocols, pharmacological profile, neuronal and glial cell types involved and means for prevention. LTP at synapses of nociceptive nerve fibres constitutes a contemporary cellular model for pain amplification following trauma, inflammation, nerve injury or withdrawal from opioids. It provides a novel target for pain therapy. This review summarizes recent progress which has been made in unravelling the properties and functions of LTP in the nociceptive system and in identifying means for its prevention and reversal.
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Extracellular nucleotides play pivotal roles in the regulation of neuronal and glial functions in the nervous system through P2X receptors (P2XRs) and P2Y receptors (P2YRs). A growing body of evidence shows that microglia express several subtypes of P2XRs and P2YRs, and that these receptors play a key role in pain signaling in the spinal cord under pathological conditions, such as following peripheral nerve injury (neuropathic pain). Following peripheral nerve injury, dorsal horn microglia become activated and show upregulated expression of purinergic receptors, and interference with the function or expression of these receptors strongly suppresses neuropathic pain. This article highlights recent advances that further increase our understanding of the mechanisms by which microglial purinergic receptors contribute to the pathogenesis of neuropathic pain.
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Curr Opin Pharmacol · Feb 2012
ReviewNeurotherapeutics to inhibit exocytosis from sensory neurons for the control of chronic pain.
There is a pressing unmet need for long-acting and effective therapeutics to alleviate symptoms of the varied forms of chronic pain. As many sufferers do not respond satisfactorily to non-addictive anti-nociceptives, a new treatment has emerged using inhibitors for the release of pain mediators from peripheral sensory nerves to give prolonged benefit. This strategy relies on proteolytically inactivating intra-neuronal SNARE (soluble N-ethylmaleimide-sensitive-factor attachment protein receptors) proteins which are essential for regulated exocytosis of transmitters, peptides and other pain signalling molecules. ⋯ Moreover, an engineered chimera of BoNT/E in which its binding domain was replaced with that from /A efficaciously inhibits the TRPV1 (transient receptor potential vanilloid type 1)-triggered release of CGRP (calcitonin gene-related peptide) from cultured sensory neurons, and suppresses the resultant excitatory effects in brain slices. A longer acting composite toxin, containing the protease of type E attached to BoNT/A, displays prolonged amelioration of pain symptoms in an animal model of inflammatory pain. This provides proof of principle that therapeutically advantageous features of /E (most robust inhibitor of CGRP release) and /A (targeting to sensory neurons and dramatic extension of the longevity of E protease) can be incorporated into a single synergistically active anti-nociceptive.
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Epigenetic changes are chemical modifications to chromatin that modulate gene activity without altering the DNA sequence. While research on epigenetics has grown exponentially over the past few years, very few studies have investigated epigenetic mechanisms in relation to pain states. However, epigenetic mechanisms are crucial to memory formation that requires similar synaptic plasticity to pain processing, indicating that they may play a key role in the control of pain states. This article reviews the early evidence suggesting that epigenetic mechanisms are engaged after injury and in chronic pain states, and that drugs used clinically to target the epigenetic machinery for the treatment of cancer might be useful for the management of chronic pain.