The journal of pain : official journal of the American Pain Society
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The glial function in morphine tolerance has been explored, but its mechanisms remain unclear. Our previous study has showed that microglia-expressed P2X7 receptors (P2X7R) contribute to the induction of tolerance to morphine analgesia in rats. This study further explored the potential downstream mechanisms of P2X7R underlying morphine tolerance. The results revealed that the blockade of P2X7 receptor by P2X7R antagonist or targeting small interfering RNA (siRNA) reduced tolerance to morphine analgesia in the pain behavioral test and spinal extracellular recordings in vivo and whole-cell recording of the spinal cord slice in vitro. Chronic morphine treatment induced an increase in the expression of interleukin (IL)-18 by microglia, IL-18 receptor (IL-18R) by astrocytes, and protein kinase Cγ (PKCγ) by neurons in the spinal dorsal horn, respectively, which was blocked by a P2X7R antagonist or targeting siRNA. Chronic morphine treatment also induced an increased release of D-serine from the spinal astrocytes. Further, both D-amino acid oxygenase (DAAO), a degrading enzyme of D-serine, and bisindolylmaleimide α (BIM), a PKC inhibitor, attenuated morphine tolerance. The present study demonstrated a spinal mechanism underlying morphine tolerance, in which chronic morphine triggered multiple dialogues between glial and neuronal cells in the spinal cord via a cascade involving a P2X7R-IL-18-D-serine-N-methyl-D-aspartate receptor (NMDAR)-PKCγ-mediated signaling pathway. ⋯ The present study shows that glia-neuron interaction via a cascade (P2X7R-IL-18-D-serine-NMDAR-PKCγ) in the spinal cord plays an important role in morphine tolerance. This article may represent potential new therapeutic targets for preventing morphine analgesic tolerance in clinical management of chronic pain.
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Vestibulodynia, the most common type of chronic vulvovaginal pain, impairs the psychological, physical health of nearly 10% of women at some point in their lifetime. The aim of this investigation was to establish reliable standardized methodologies for assessment of pain sensitivity in vulvar mucosa and pelvic musculature. We enrolled 34 women with vestibulodynia and 21 pain-free controls. The participants underwent a nuanced exam that consisted of palpation of precisely located vulvar mucosal and pelvic muscle sites. These measurements remained highly stable when participants were reexamined after 2 weeks, with high within-examiner correlation. Vestibulodynia patients reported greater sensitivity than pain-free controls at the majority of examination sites, particularly at mucosal sites on the lower vestibule. The pain threshold measures at the lower mucosal sites were also associated with the participants' self-reported pain levels during intercourse. These mucosal pain threshold measurements were used to discriminate between vestibulodynia cases and controls with high sensitivity and specificity. This data supports the feasibility of contemporaneous assessment of vulvar mucosa and underlying musculature in the pelvic region, offering the hope of a more precise case definition for vestibulodynia and related disorders. ⋯ This study describes performance characteristics of novel methodologies for assessing pelvic muscle and mucosal sensitivity. These pain sensitivity measures were reproducible and associated with subjective pain reports and vestibulodynia case status and represent an important step toward a more precise case definition for vestibulodynia and related disorders.
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Transcutaneous electrical nerve stimulation (TENS) reduces hyperalgesia and pain. Both low-frequency (LF) and high-frequency (HF) TENS, delivered at the same intensity (90% motor threshold [MT]) daily, result in analgesic tolerance with repeated use by the fifth day of treatment. The current study tested 1) whether increasing intensity by 10% per day prevents the development of tolerance to repeated TENS; and 2) whether lower intensity TENS (50% MT) produces an equivalent reduction in hyperalgesia when compared to 90% MT TENS. Sprague-Dawley rats with unilateral knee joint inflammation (3% carrageenan) were separated according to the intensity of TENS used: sham, 50% LF, 50% HF, 90% LF, 90% HF, and increased intensity by 10% per day (LF and HF). The reduced mechanical withdrawal threshold following the induction of inflammation was reversed by application of TENS applied at 90% MT intensity and increasing intensity for the first 4 days. On the fifth day, the groups that received 90% MT intensity showed tolerance. Nevertheless, the group that received an increased intensity on each day still showed a reversal of the mechanical withdrawal threshold with TENS. These results show that the development of tolerance can be delayed by increasing intensity of TENS. ⋯ Our results showed that increasing intensity in both frequencies of TENS was able to prevent analgesic tolerance. Results from this study suggest that increasing intensities could be a clinical method to prevent analgesic tolerance and contribute to the effective use of TENS in reducing inflammatory pain and future clinical trials.