PSX-A-2 Late-Breaking: Acute Endotoxinemia May Increase Intercostal Temporary Mechanical Nociception in Wethers

Systemic inflammation induced by lipopolysaccharide (LPS; endotoxin) is associated with generalized hyperalgesia in humans and some animal models. However, the effects of endotoxin-induced inflammation on pain threshold in livestock, such as sheep, is unknown. Eight wethers [~1 year of age; 61.3 ± 0.5 kg BW] were administered saline (2 mL; n = 4) or endotoxin (2 mL; 400 ng of LPS / kg BW; n = 4) intravenously. A handheld algometric unit was used to administer temporary mechanical nociception (TMN) before (Day -2) and after (Day 1) treatment administration by the same person three times at two locations on the right thorax (intercostal spaces 6 and 9). Two-way ANOVA was completed in SAS v9.4 (Cary, NC). There were effects of day (P < 0.001) and location (P < 0.0001) on TMN, such that the force needed to induce TMN on Day -2 (2.04 +/- 0.15 kgF) was less than on Day 1 (2.93 +/- 0.15 kgF) and the force needed to induce TMN at intercostal space 6 (1.81 +/- 0.15 kgF) was less than at intercostal space 9 (3.15 +/- 0.15 kgF). While there was no effect of treatment (P = 0.96), or interaction of treatment and location (P = 0.19), day and location (P = 0.25), or treatment and day and location (P = 0.49), there was a tendency for an interaction of treatment and day (P = 0.06), such that TMN was not different on Day 1 (2.73 +/- 0.30 kgF) and Day -2 (2.24 +/- 0.30 kgF) for animals receiving saline but was greater on Day 1 (3.12 +/- 0.30 kgF) than Day -2 (1.83 +/- 0.30 kgF) for animals receiving LPS. While systemic inflammation is associated with reduced pain threshold in some models, acute LPS-induced inflammation may increase intercostal TMN in castrated sheep.

Early maternal separation accelerates the progression of endometriosis in adult mice

Background A large body of research highlights the importance of early-life environmental impact on the health outcome in adulthood. However, whether early-life adversity (ELA) has any impact on the development of endometriosis is completely unclear. In this study, we tested the hypothesis that ELA, as manifested by neonatal separation, can accelerate the progression of endometriosis in mouse through activation of the adrenergic receptor β2 (ADRB2) signaling pathway, leading to increased angiogenesis and progression of endometriotic lesions. Methods Eight female Balb/C mice, in late pregnancy, were used used for this study, which later gave birth to 22 female newborn pubs. Eleven additional female Balb/C mice were also used as donors of uterine tissues. The 22 newborn pubs were randomly divided into 2 equal-sized groups, maternal separation (MS) and no separation (NS). Pubs in the MS group were separated from their dams for 3 h/day from postnatal day (PND) 1 to 21, while those in the NS control remained in the home cage with their dams. In adulthood (8-week old), 3 mice in each group were randomly selected to undergo a battery of behavior tests. The remaining 8 mice in each group were induced with endometriosis by intraperitoneal injection of uterine fragments from donor mice. Four weeks after the induction, all mice were sacrificed and their endometriotic lesions were excised for quantification and then prepared for immunohistochemistry analysis. Results We confirmed that MS during infancy resulted in anxiety and depression-like behaviors as previously reported. We also found that in MS mice the lesion weight was increased by over 2 folds and generalized hyperalgesia was also significantly increased as compared with NS mice. Immunostaining analysis demonstrated that MS accelerated the development of endometriosis likely through decreased dopamine receptor D2 (DRD2) expression and activation of the ADRB2/cAMP-response element binding protein (CREB) signaling pathway, leading to increased angiogenesis and progression of endometriotic lesions. Conclusions Exposure of female mouse pups to ELA such as MS during their infancy period accelerates the progression of endometriosis, possibly through altered neuronal wiring and hyperactivity of the hypothalamic-pituitary-adrenal axis.

Phantom limb pain intensity is associated with generalized hyperalgesia

After limb amputation, most amputees suffer from phantom limb pain (PLP). The mechanisms underlying this condition are complex and insufficiently understood. Altered somatosensory sensitivity (either heightened or lowered) might contribute to PLP. Recent studies have tested this assumption but mainly focused on the residual limb. However, altered somatosensation in PLP might be generalized. In this study, we applied quantitative sensory testing to 37 unilateral upper-limb amputees (23 with PLP, 14 without PLP) and 19 healthy controls. We assessed thresholds to heat pain (HPT), pressure pain (PPT), warmth detection (WDT), and two-point discrimination (2PDT) at the residual limb, a homologous point and the thenar of the intact limb, and both corners of the mouth. We did not find significant differences in any of the thresholds between the groups. However, higher PLP intensity was significantly related to lower HPT at all measured body sites except for the residual limb. At the residual limb, lower HPT were observed in more distal amputations and in amputees showing a higher degree of prosthesis use. Although WDT did by itself not significantly correlate with PLP intensity at any of the body sites, multiple regression analysis showed the highest multiple correlations with PLP intensity for a combination of high WDT and low HPT at the corners of the mouth. In this model, the combination of HPT and WDT shared 58% of the variance with PLP intensity. Other factors of potential importance, especially residual limb pain, were not significantly associated to any sensory threshold. We conclude that the intensity, but not the presence of PLP is positively associated with higher heat pain sensitivity. Since this association was observed at various, distributed body sites, we suggest that central mechanisms might be underlying such generalized hyperalgesia.

Treatment response and central pain processing in Anterior Cutaneous Nerve Entrapment Syndrome: An explorative study

Background10–30% of chronic abdominal pain originates in the abdominal wall. A common cause for chronic abdominal wall pain is the Anterior Cutaneous Nerve Entrapment Syndrome (ACNES), in which an intercostal nerve branch is entrapped in the abdominal rectus sheath. Treatment consists of local anaesthetics and neurectomy, and is ineffective in 25% of cases for yet unknown reasons.In some conditions, chronic pain is the result of altered pain processing. This so-called sensitization can manifest as segmental or even generalized hyperalgesia, and is generally difficult to treat.ObjectiveThe aim of this study was to assess pain processing in ACNES patients responsive and refractory to treatment by using Quantitative Sensory Testing, in order to explore whether signs of altered central pain processing are present in ACNES and are a possible explanation for poor treatment outcomes.Methods50 patients treated for ACNES with locally orientated treatment were included. They were allocated to a responsive or refractory group based on their response to treatment. Patients showing an improvement of the Visual Analogue Scale (VAS) pain score combined with a current absolute VAS of <40 mm were scored as responsive.Sensation and pain thresholds to pressure and electric skin stimulation were determined in the paravertebral bilateral ACNES dermatomes and at four control areas on the non-dominant side of the body, i.e. the musculus trapezius pars medialis, musculus rectus femoris, musculus abductor hallucis and the thenar. The ACNES dermatomes were chosen to signal segmental hyperalgesia and the sum of the control areas together as a reflection of generalized hyperalgesia. Lower thresholds were interpreted as signs of sensitized pain processing. To test for alterations in endogenous pain inhibition, a conditioned pain modulation (CPM) response to a cold pressor task was determined. Also, patients filled in three pain-related questionnaires, to evaluate possible influence of psychological characteristics on the experienced pain.ResultsPatients refractory to treatment showed significantly lower pressure pain thresholds in the ACNES dermatomes and for the sum of as well as in two individual control areas. No differences were found between groups for electric thresholds or CPM response. Duration of complaints before diagnosis and treatment was significantly longer in the refractory compared to the responsive group, and refractory patients scored higher on the pain-related psychological surveys.Conclusion and ImplicationsIn this hypothesis-generating exploratory study, ACNES patients refractory to treatment showed more signs of sensitized segmental and central pain processing. A longer duration of complaints before diagnosis and treatment may be related to these alterations in pain processing, and both findings could be associated with less effective locally orientated treatment. In order to validate these hypotheses further research is needed.Registration numberNCT01920880 (Clinical Trials Register; http://www.clinicaltrials.gov).