Mol Pain
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Various small molecules act as neurotransmitters and orchestrate neural communication. Growing evidence suggests that not only classical neurotransmitters but also several small molecules, including amino acid derivatives, modulate synaptic transmission. As conditions of acute and chronic pain alter neuronal excitability in the nucleus accumbens, we hypothesized that small molecules released in the nucleus accumbens might play important roles in modulating the pain sensation. ⋯ We identified N-acetylaspartylglutamate as a potential pain modulator that is endogenously released in the nucleus accumbens. Infusion of N-acetylaspartylglutamate into the nucleus accumbens significantly attenuated the pain induced by the activation of sensory nerves through optical stimulation. These findings suggest that N-acetylaspartylglutamate released in the nucleus accumbens could modulate pain sensation.
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Cooling temperatures and low pH have profound effects on somatosensory functions including nociception. The effects not only can be mediated by cooling temperature transducers and proton transducers expressed in subpopulations of somatosensory neurons but may also be mediated by ion channels involving membrane excitability such as voltage-dependent K+ channels in somatosensory neurons. In the present study, we performed the in situ patch-clamp recordings from nociceptive-like trigeminal ganglion neurons in ex vivo trigeminal ganglion preparations of adult rats. ⋯ Cooling temperatures and low pH suppressed voltage-activated inward Na+ currents and also voltage-dependent outward K+ currents in nociceptive-like trigeminal ganglion neurons. Voltage-dependent outward K+ currents in nociceptive-like trigeminal ganglion neurons consist of inactivating A-type K+ currents and non-inactivating type K+ currents, and the former were more sensitive to cooling temperatures and low pH. Collectively, suppressing multiple types of K+ channels may be associated with the enhanced excitability of nociceptive trigeminal ganglion neurons by cooling temperatures and low pH.
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Pain hypersensitivity resulting from peripheral nerve injury depends on pathological microglial activation in the dorsal horn of the spinal cord. This microglial activity is critically modulated by P2X7 receptors (P2X7R) and ATP stimulation of these receptors produces mechanical allodynia, a defining feature of neuropathic pain. Peripheral nerve injury increases P2X7R expression and potentiates its cation channel function in spinal microglia. ⋯ Intrathecal administration of this palmitoylated peptide (P2X7R379-389) transiently reversed mechanical allodynia caused by peripheral nerve injury in both male and female rats. Furthermore, targeting Y382-384 suppressed P2X7R-mediated release of cytokine tumor necrosis factor alpha and blocked the adoptive transfer of mechanical allodynia caused by intrathecal injection of P2X7R-stimulated microglia. Thus, Y382-384 site-specific modulation of P2X7R is an important microglial mechanism in neuropathic pain.
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Background Diabetic neuropathic pain is poorly controlled by analgesics, and the precise molecular mechanisms underlying hyperalgesia remain unclear. The KCNQ2/3/5 channels expressed in dorsal root ganglion neurons are important in pain transmission. The expression and activity of KCNQ2/3/5 channels in dorsal root ganglion neurons in rats with diabetic neuropathic pain were investigated in this study. ⋯ Administration of retigabine alleviated both mechanical allodynia and thermal hyperalgesia, while XE991 augmented both mechanical allodynia and thermal hyperalgesia in diabetic neuropathic pain in rats. Conclusion The findings elucidate the mechanisms by which downregulation of the expression and reduction of the activity of KCNQ2/3/5 channels in diabetic rat dorsal root ganglion neurons contribute to neuronal hyperexcitability, which results in hyperalgesia. These data provide intriguing evidence that activation of KCNQ2/3/5 channels might be the potential new targets for alleviating diabetic neuropathic pain symptoms.
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Meta Analysis Comparative Study
Comparison of the efficacy and safety of non-steroidal anti-inflammatory drugs for patients with primary dysmenorrhea: A network meta-analysis.
Objective Non-steroidal anti-inflammatory drugs are used as first-line treatment of primary dysmenorrhea, but there has been no optimal clinical choice among non-steroidal anti-inflammatory drugs yet. The present study was to assess the relative benefits of different common non-steroidal anti-inflammatory drugs for primary dysmenorrhea patients with a network meta-analysis. Methods Randomized controlled trials were screened by our criteria and included in the network meta-analysis. ⋯ According to the results of network analysis and surface under cumulative ranking curve, flurbiprofen was considered to be the best one among all the treatments in efficacy, and aspirin was worse than most of others. On the other hand, tiaprofenic acid and mefenamic acid were indicated as the safest drugs. Conclusion Considering the efficacy and safety, we recommended flurbiprofen and tiaprofenic acid as the optimal treatments for primary dysmenorrhea.