Pain
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The aim of the study was to investigate whether cortical response to a repeated noxious procedure may change over time in preterm infants. Possible reasons for change are: (1) advancing maturation of central nervous system; and (2) increasing experience with noxious procedures during hospital stay. Sixteen preterm infants were recruited, with a postmenstrual age (PMA) ranging between 29 and 36 weeks. ⋯ Conversely, the degree of cortical activation decreased as the number of noxious events increased (P < 0.002). We conclude the following: (1) Preterm newborns showed a significant activation of the posterior frontal cortex in association with noxious stimuli; (2) Cortical activation was progressively greater with increasing PMA; (3) There was an inverse relationship between cortical activation and the number of heel pricks. We speculate that such findings may be due to both endogenous cortical maturation and experience-dependent neuroplasticity of the developing brain (eg, synaptogenesis, synaptic pruning).
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Repeated sensory exposures shape the brain's function and its responses to environmental stimuli. An important clinical and scientific question is how exposure to pain affects brain network activity and whether that activity is modifiable with training. We sought to determine whether repeated pain exposure would impact brain network activity and whether these effects can be reversed by cognitive behavioral therapy (CBT)-based training. ⋯ Finally, the regulate group showed enhanced resting functional connectivity between areas of the DMN and executive control network over time, compared with the control group. Our study demonstrates that trainable cognitive states can alter the effect of repeated sensory exposure on the brain. The findings point to the potential utility of cognitive training to prevent changes in brain network connectivity that occur with repeated experience of pain.
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Uncoupling the protein-protein interaction between collapsin response mediator protein 2 (CRMP2) and N-type voltage-gated calcium channel (CaV2.2) with an allosteric CRMP2-derived peptide (CBD3) is antinociceptive in rodent models of inflammatory and neuropathic pain. We investigated the efficacy, duration of action, abuse potential, and neurobehavioral toxicity of an improved mutant CRMP2 peptide. A homopolyarginine (R9)-conjugated CBD3-A6K (R9-CBD3-A6K) peptide inhibited the CaV2.2-CRMP2 interaction in a concentration-dependent fashion and diminished surface expression of CaV2.2 and depolarization-evoked Ca influx in rat dorsal root ganglia neurons. ⋯ Continuous subcutaneous infusion of R9-CBD3-A6K over a 24- to 72-hour period reversed tactile allodynia and ongoing pain, demonstrating a lack of tolerance over this time course. Importantly, continuous infusion of R9-CBD3-A6K did not affect motor activity, anxiety, depression, or memory and learning. Collectively, these results validate the potential therapeutic significance of targeting the CaV-CRMP2 axis for treatment of neuropathic pain.
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Despite being one of the first-choice analgesics for chronic neuropathic pain, gabapentin sometimes fails to provide analgesia, but the mechanisms for this lack of efficacy is unclear. Rats with nerve injury including L5-L6 spinal nerve ligation (SNL) respond uniformly and well to gabapentin, but many of these studies are performed within just a few weeks of injury, questioning their relevance to chronic neuropathic pain. In this study, intraperitoneal gabapentin showed a time-dependently reduction in antihypersensitivity after SNL, associated with downregulation of astroglial glutamate transporter-1 (GLT-1) in the locus coeruleus (LC). ⋯ Knock-down of GLT-1 in the LC reversed the effect of valproate to restore gabapentin-induced antihypersensitivity. In addition, the antihypersensitivity effect of the intrathecal α2-adrenoceptor agonist clonidine also decreased with time after SNL injury. These results suggest that downregulation of GLT-1 in the LC and reduced spinal noradrenergic inhibition contribute to impaired analgesic efficacy from gabapentin in chronic neuropathic pain and that valproate can rescue this impaired efficacy.
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Despite the large number of studies addressing how prolonged painful stimulation affects brain functioning, there are only a handful of studies aimed at uncovering if persistent conditions of reduced pain perception would also result in brain plasticity. Permanent hypoalgesia induced by neonatal injection of capsaicin or carrageenan has already been shown to affect learning and memory and to induce alterations in brain gene expression. In this study, we used the Prrxl1 model of congenital mild hypoalgesia to conduct a detailed study of the neurophysiological and behavioral consequences of reduced pain experience. ⋯ Importantly, although inflammatory pain by Complete Freund Adjuvant injection caused a decrease in fronto-hippocampal connectivity in the wild-type animals, Prrxl1 mice maintained the baseline levels. The onset of inflammatory pain also reverted the differences in forebrain expression of stress- and monoamine-related genes in Prrxl1 mice. Altogether our results suggest that congenital hypoalgesia may have an effect on brain plasticity that is the inverse of what is usually observed in animal models of chronic pain.