Pain
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The mechanisms underlying trigeminal pain conditions are incompletely understood. In vitro animal studies have elucidated various targets for pharmacological intervention; however, a lack of clinical models that allow evaluation of viable innervated human tissue has impeded successful translation of many preclinical findings into clinical therapeutics. Therefore, we developed and characterized an in vitro method that evaluates the responsiveness of isolated human nociceptors by measuring basal and stimulated release of neuropeptides from collected dental pulp biopsies. ⋯ Superfusion with phorbol 12-myristate 13-acetate (PMA) increased basal and stimulated release, whereas PGE2 augmented only basal release. Compared with vehicle treatment, pretreatment with PGE2 induced competence for DAMGO to inhibit capsaicin-stimulated iCGRP release, similar to observations in animal models where inflammatory mediators induce competence for opioid inhibition. These results indicate that the release of iCGRP from human dental pulp provides a novel tool to determine the effects of pharmacological compounds on human nociceptor sensitivity.
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Clinical Trial
Prospective judgments of acceptable outcomes for pain, interference and activity: Patient-determined outcome criteria.
The selection of outcome criteria for chronic pain, both the domain of measurement and the magnitude of change, in RCTs is largely determined by the investigators. The present study investigated patient-determined criteria for the magnitude of change necessary to achieve an 'acceptable outcome' (endpoint) on the brief pain inventory and two subscales of the multidimensional pain inventory. Seventy-eight patients attending a chronic pain out-patient clinic were asked to rate their current state on the measures and then complete the scales as they would if treatment were to result in an acceptable outcome. ⋯ Neither adequately fit the data. There were discrepancies between the patients' judgments of acceptable outcomes and the RCI and SCS criteria. Suggestions for future research and possible clinical implications are discussed.
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Comparative Study
Exploring relationships for visceral and somatic pain with autonomic control and personality.
The autonomic nervous system (ANS) integrates afferent and motor activity for homeostatic processes including pain. The aim of the study was to compare hitherto poorly characterised relations between brainstem autonomic control and personality in response to visceral and somatic pain. Eighteen healthy subjects (16 females, mean age 34) had recordings during rest and pain of heart rate (HR), cardiac vagal tone (CVT), cardiac sensitivity to baroreflex (CSB), skin conductance level (SC), cardiac sympathetic index (CSI) and mean blood pressure (MBP). ⋯ Visceral pain-related parasympathetic change correlated with personality. ANS defence responses are nuanced and may relate to personality type for visceral pain. Clinical relevance of these findings warrants further exploration.
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It is widely appreciated that there is significant inter-individual variability in pain sensitivity, yet only a handful of contributing genetic variants have been identified. Computational genetic mapping and quantitative trait locus analysis suggested that variation within the gene coding for the beta3 subunit of the Na+,K+-ATPase pump (Atp1b3) contributes to inter-strain differences in the early phase formalin pain behavior. ⋯ Furthermore, in vivo siRNA knockdown of the beta3 subunit produced strain-specific changes in the early phase pain response, completely rescuing the strain difference. These findings indicate that the beta3 subunit of the Na+,K+-ATPase is a novel determinant of nociceptive sensitivity and further supports the notion that pain variability genes can have very selective effects on individual pain modalities.
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Tibia fracture in rats initiates a syndrome resembling the complex regional pain syndrome type I. Accumulating evidence indicates that IL-1beta is involved in the modulation of nociceptive information and it acts as an intermediate inflammatory mediator via up-regulation of NGF. We hypothesized that IL-1beta signaling might mediate the development of the CRPS-like changes after tibial fracture, either directly or by stimulating NGF expression. ⋯ We found that: (1) IL-1ra reduced fracture-induced nociceptive sensitization, but did not decrease hindpaw edema or warmth, (2) fracture chronically up-regulated IL-1beta mRNA and protein expression in hindpaw skin keratinocytes, (3) IL-1beta intraplantar injection induced mechanical allodynia in a dose-dependent manner and stimulated keratinocyte NGF expression in the hindpaw skin, and (4) intraplantar injection of NGF-induced nociceptive sensitization. Collectively, these results indicate that cutaneous IL-1beta signaling can contribute to chronic regional nociceptive sensitization after fracture, possibly by stimulating NGF over-expression in keratinocytes. Our data also highlight the importance of the keratinocyte as the primary source of post-traumatic IL-1beta over-expression.