Pain
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Chronic pain is a major characteristic feature of sickle cell disease (SCD). The refractory nature of pain and the development of chronic pain syndromes in many patients with SCD suggest that central neural mechanisms contribute to pain in this disease. We used HbSS-BERK sickle mice, which show chronic features of pain similar to those observed in SCD, and determined whether sensitization of nociceptive neurons in the spinal cord contributes to pain and hyperalgesia in SCD. ⋯ Compared with control HbAA-BERK mice, nociceptive dorsal horn neurons in sickle mice exhibited enhanced excitability as evidenced by enlarged receptive fields, increased rate of spontaneous activity, lower mechanical thresholds, enhanced responses to mechanical stimuli, and prolonged afterdischarges following mechanical stimulation. These changes were accompanied by increased phosphorylation of mitogen-activated protein kinases (MAPKs) in the spinal cord that are known to contribute to neuronal hyperexcitability, including c-Jun N-terminal kinase (JNK), p44/p42 extracellular signaling-regulated kinase (ERK), and p38. These findings demonstrate that central sensitization contributes to pain in SCD.
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Transient receptor potential vanilloid 1 (TRPV1) receptors are expressed in nociceptive neurons of rat dorsal root ganglions (DRGs) and mediate inflammatory pain. Nonspecific inhibition of protein-tyrosine phosphatases (PTPs) increases the tyrosine phosphorylation of TRPV1 and sensitizes TRPV1. However, less is known about tyrosine phosphorylation's implication in inflammatory pain, compared with that of serine/threonine phosphorylation. ⋯ Complete Freund's adjuvant (CFA)-induced inflammatory pain in rats significantly increased the expression of Shp-1, TRPV1, and tyrosine-phosphorylated TRPV1, as well as the colocalization of Shp-1 and TRPV1 in DRGs. Intrathecal injection of sodium stibogluconate aggravated CFA-induced inflammatory pain, whereas Shp-1 overexpression in DRG neurons alleviated it. These results suggested that Shp-1 dephosphorylated and inhibited TRPV1 in DRG neurons, contributing to maintain thermal nociceptive thresholds in normal rats, and as a compensatory mechanism, Shp-1 increased in DRGs of rats with CFA-induced inflammatory pain, which was involved in protecting against excessive thermal hyperalgesia.
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Responses to pharmacotherapy for acute and chronic pain are highly variable, and efficacy is often compromised by some form of toxicity. To increase our understanding of complexities of pharmacotherapy, the authors discuss an approach to identify analgesic responder subgroups and predictors of response. Additionally, analgesic efficacy and toxicity were combined in a single risk-benefit index (utility function) to quantify the probability of side effects in high- vs low-analgesic responders. ⋯ An important observation was that, irrespective of dose, low-analgesic responders to fentanyl had a greater probability of respiratory depression than analgesia while the reverse was true for high-analgesic responders. These data show dissociation between 2 μ-opioid end-points and explain the danger of treating poor analgesic responders with increasingly higher opioid doses. Apart from being valuable in drug development programs, the outlined approach can be used to determine the choice of drug and dose in the treatment of pain in patients with potent and toxic analgesics.
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An important property of the nociceptive system is its plasticity, ie, the ability to change in an experience-dependent manner, which is implicated in the transition from acute pain to chronic pathological pain. Disease-induced plasticity can occur at both structural and functional levels and manifests as changes in individual molecules, synapses, cellular function, and network activity. In this short review, the author discusses how synaptic plasticity may mediate pathophysiological alterations linked to chronic pain by virtue of shifting the balance between excitation and inhibition, with a particular emphasis on the spinal dorsal horn. ⋯ Structural remodeling and reorganization represent another exciting area of advance in our understanding of pain. Here, new insights into maladaptive structural plasticity of spinal synapses and molecular determinants thereof will be discussed. Finally, the role of synapse-to-nucleus communication in mediating long-term changes in nociceptive sensitivity is discussed from the view point of pain chronicity.