A Pusher and a Clip Applied to Hind Paws Under Isoflurane Sedation to Evaluate Neuropathic Pain in a CCI Model

: Rodent behavior assessments have been developed to evaluate pain. However, their fidgety activity and reactivity to human contact make it hard to activate animals in a consistent manner and get uniform and trustworthy responses. The present study was performed on prairie voles (aged 8 weeks). Sham (7 male prairie voles) and chronic constriction injury (CCI) (8 male prairie voles) rodents were investigated before surgery and four and seven days later. Each animal was assessed for nociceptive behavior. Pressure and mechanical threshold tests were conducted by the application of three different pushers to the center of hind paws and arterial clips to the toes while sedated with isoflurane. The CCI affected right lower extremity prominently increased nociceptive behavior scores four and seven days after the experiment, and the CCI affected right hind paw prominently decreased pressure and mechanical threshold tests four and seven days after the experiment . The pressure and mechanical thresholds were relevant to the scorings of nociceptive behavior in CCI model animals.

Brief communication: Weak control of snow avalanche deposit volumes by avalanche path morphology

Snow avalanches are a major component of the mountain cryosphere, but little is known about the factors controlling the variability of their deposit volumes. This study investigates the influence of avalanche path morphology on ca. 1500 deposit volumes recorded between 2003 and 2018 in 77 snow avalanche paths of the French Alps. Different statistical techniques show a slight but significant link between deposit volumes and path mean elevation and orientation, with contrasted patterns between winter and spring seasons. The limited and partially non-linear nature of this control may result from the combined influence on the genesis of deposit volumes of mean path activity, climate conditions, and mechanical thresholds determining avalanche release.

Use of mechanical thresholds in a model of feline clinical acute pain and their correlation with the Glasgow Feline Composite Measure Pain Scale scores

Objectives The aim of this study was to evaluate the use of mechanical thresholds (MT), measured with the SMALGO (Small Animal ALGOmeter), and to determine whether there was a correlation between MT and Glasgow Feline Composite Measure Pain Scale (CMPS–Feline) scores in cats undergoing ovariohysterectomy. Methods Client-owned cats undergoing flank ovariohysterectomy were recruited. Pain scores for the pre- and postoperative periods were obtained using the CMPS-Feline in each cat by two independent investigators (A and B). Following CMPS–Feline scoring, MT were measured with the SMALGO, in the surgical area, pre- and postoperatively, only by investigator A. Each cat served as its own control for the comparison of pre- and postoperative variables. Reliability statistics were used to assess the level of inter-observer agreement (A vs B) with respect to pre- and postoperative CMPS–Feline scores, while Spearman’s correlation statistics were used to analyse the relationship between MT and CMPS–Feline scores. Results Twenty-nine cats completed the study. Preoperative MT (340 g [range 108–691]) were significantly higher than postoperatively (233 g [range 19–549]; P = 0.001). CMPS–Feline scores were not found to differ significantly between the preoperative period (2 [range 0–7] for investigator A and 3.2 ± 2.3 for investigator B) and postoperative period (2 [range 0–10] for investigator A and 3 [range 0–8] for investigator B) for either investigator. Reliability statistics revealed that the level of inter-observer agreement with respect to CMPS–Feline was fair for the preoperative assessments but poor for the postoperative evaluations. There was no correlation between MT and CMPS-Feline scores. Conclusions and relevance Although there was no correlation with CMPS–Feline scores performed at the same timepoint, MT increased postoperatively vs baseline. Assuming that, despite analgesia, susceptibility of the surgical area to mechanical stimulation would increase after surgery, this finding suggests that MT might be useful to assess feline surgical pain. The poor level of inter-observer agreement with respect to postoperative CMPS–Feline scores highlights the potential limitations of this scale.

Brief communication: Weak control of snow avalanche deposit volumes by paths morphological characteristics

Snow avalanches are a major component of the mountain cryosphere, but little is known about the factors controlling the variability of their deposit volumes. This study investigates the influence of morphological characteristics on c. 1500 deposit volumes recorded between 2003 and 2018 in 77 snow avalanche paths of the French Alps. Different statistical techniques show a slight but significant link between deposit volumes and path mean elevation and orientation, with contrasted patterns between winter and spring seasons. The weakness, partially non-linear nature of this control may result from the combined influence on the genesis of deposit volumes of mean path activity, climate conditions and mechanical thresholds determining avalanche release.

The IL33 receptor ST2 contributes to mechanical hypersensitivity in mice with neuropathic pain

Pathogen infection triggers pain via activation of the innate immune system. Toll-like receptors (TLRs) and Nod-like receptors (NLRs) are the main components of innate immunity and have been implicated in pain signaling. We previously revealed that the TLR2-NLRP3-IL33 pathway mediates inflammatory pain responses during hyperactivity of innate immunity. However, their roles in neuropathic pain had remained unclear. Here we report that although knockout of TLR2 or NLRP3 does not affect spared nerve injury (SNI)-induced neuropathic pain, intrathecal inhibition of IL33/ST2 signaling with ST2 neutralizing antibodies reverses mechanical thresholds in SNI mice compared to PBS vehicle treated animals. This effect indicates a universal role of IL33 in both inflammatory and neuropathic pain states, and that targeting the IL33/ST2 axis could be a potential therapeutic approach for pain treatment.

Lateralized decrease of parvalbumin+ cells in the somatosensory cortex of ASD models is correlated with unilateral tactile hypersensitivity

Inhibitory control of excitatory networks contributes to cortical functions. Increasing evidence indicates that parvalbumin expressing (PV+) basket cells (BC) are a major player in maintaining the balance between excitation (E) and inhibition (I) in the cortex. Disruption of E/I balance in cortical networks is believed to be a hallmark of autism spectrum disorders (ASD) and may contribute to sensory alterations seen in ASD. Here, we report a lateralized decrease in the number of PV+ BCs in L2/3 of the somatosensory cortex in the dominant hemisphere of adult Shank3-/- and Cntnap2-/- mouse models of ASD. The dominant hemisphere was identified during a reaching task to establish each animal’s dominant forepaw. Double labeling with anti-PV antibody and a biotinylated lectin (i.e., VVA) showed that the number of BCs was not different but rather, some BCs did not express detectable levels of PV (PV-), resulting in an elevated number of PV- VVA+ basket cells. This lateralized reduction was not observed in the number of interneurons from the other two major groups that express somatostatin or the serotonergic receptor 5HT3a. Finally, we showed that dominant hind paws had higher mechanical sensitivity (i.e., lower mechanical thresholds measured with von Frey test) but no difference in thermal sensitivity (measured with Hargreaves test) when compared to the other hind paw. This mechanical hypersensitivity in the dominant paw correlated with the decrease in the number of PV+ interneurons and reduced PV expression in the corresponding cortex. Together, these results suggest that the sensory hypersensitivity in ASD could be due to decreased inhibitory inputs to the dominant somatosensory cortex.

The Actions and Mechanisms of P2X7R and p38 MAPK Activation in Mediating Bortezomib-Induced Neuropathic Pain

The proteasome inhibitor bortezomib (BTZ) is a potent first-line anticancer drug for multiple myeloma; nonetheless, it induced peripheral neuropathy. It has been suggested that many cytokines may play a role in mediating neuropathic pain, but the underlying molecular mechanism is not fully understood. Recent studies have shown that neuropathic pain is closely related to the purinergic ligand-gated ion channel 7 receptor (P2X7R), one of the P2X receptors, which is richly expressed in glial cells. P2X7-p38 pathway is correlated with microglia- and satellite glial cell- (SGC-) mediated neuropathic pain. However, the association of P2X7R and p38MAPK in mediating BTZ-induced neuropathic pain remains unclear. In this study, the relationship between P2X7R activation and p38 phosphorylation in the dorsal root ganglion (DRG) and spinal dorsal horn (SDH) in the development and maintenance of BTZ-induced neuropathic pain was elucidated. The results showed that BTZ increased mechanical thresholds in rats, accompanied with upregulation of P2X7R expression and p38MAPK phosphorylation, indicating that P2X7R and p38MAPK are key molecules in the development and maintenance of BTZ-induced neuropathic pain. Inhibiting p38MAPK phosphorylation with SB203580 resulted in downregulation of P2X7R expression levels. Inhibition of P2X7R with Brilliant Blue G (BBG) reversed neuropathic pain might decrease through the expression of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and IL-6 via inhibiting p38MAPK phosphorylation. The P2X7R/p38MAPK signaling pathway in SGCs of DRG and microglia of SDH might be a potential pharmacological target behind this mechanism as an opportunity to relieve BTZ-induced neuropathic pain.

Shift of µ-opioid Receptor Signaling in the Dorsal Reticular Nucleus Is Implicated in Morphine-induced Hyperalgesia in Male Rats

Background Increased descending pain facilitation accounts for opioid-induced hyperalgesia, but the underlying mechanisms remain elusive. Given the role of µ-opioid receptors in opioid-induced hyperalgesia in animals, the authors hypothesized that the dorsal reticular nucleus, a medullary pain facilitatory area, is involved in opioid-induced hyperalgesia through altered µ-opioid receptor signaling. Methods The authors used male Wistar rats (n = 5 to 8 per group), chronically infused with morphine, to evaluate in the dorsal reticular nucleus the expressions of the µ-opioid receptor and phosphorylated cAMP response element-binding, a downstream marker of excitatory µ-opioid receptor signaling. The authors used pharmacologic and gene-mediated approaches. Nociceptive behaviors were evaluated by the von Frey and hot-plates tests. Results Lidocaine fully reversed mechanical and thermal hypersensitivity induced by chronic morphine. Morphine-infusion increased µ-opioid receptor, without concomitant messenger RNA changes, and phosphorylated cAMP response element-binding levels at the dorsal reticular nucleus. µ-opioid receptor knockdown in morphine-infused animals attenuated the decrease of mechanical thresholds and heat-evoked withdrawal latencies compared with the control vector (von Frey [mean ± SD]: −17 ± 8% vs. −40 ± 9.0%; P < 0.001; hot-plate: −10 ± 5% vs. −32 ± 10%; P = 0.001). µ-opioid receptor knockdown in control animals induced the opposite (von Frey: −31 ± 8% vs. −17 ± 8%; P = 0.053; hotplate: −24 ± 6% vs. −3 ± 10%; P = 0.001). The µ-opioid receptor agonist (D-ALA2,N-ME-PHE4,GLY5-OL)-enkephalin acetate (DAMGO) decreased mechanical thresholds and did not affect heat-evoked withdrawal latencies in morphine-infused animals. In control animals, DAMGO increased both mechanical thresholds and heat-evoked withdrawal latencies. Ultra-low-dose naloxone, which prevents the excitatory signaling of the µ-opioid receptor, administered alone, attenuated mechanical and thermal hypersensitivities, and coadministered with DAMGO, restored DAMGO analgesic effects and decreased phosphorylated cAMP response element-binding levels. Conclusions Chronic morphine shifted µ-opioid receptor signaling from inhibitory to excitatory at the dorsal reticular nucleus, likely enhancing descending facilitation during opioid-induced hyperalgesia in the rat. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

Regulatory Effects of Propofol on High-Dose Remifentanil-Induced Hyperalgesia

We aimed to evaluate the regulatory effects of propofol on high-dose remifentanil-induced hyperalgesia. A total of 180 patients receiving laparoscopic cholecystectomy were randomly divided into sevoflurane + high-dose remifentanil (SH) group, sevoflurane + low-dose remifentanil (SL) group and propofol + high-dose remifentanil group (PH) group (n=60). After intravenous administration of midazolam, SH and SL groups were induced with sevoflurane and remifentanil, and PH group was induced with propofol and remifentanil. During anesthesia maintenance, SH and SL groups were given 0.3 μg/kg/min and 0.1 μg/kg/min sevoflurane and remifentanil respectively, and PH group was given 0.3 μg/kg/min propofol and remifentanil. The three groups had significantly different awakening time, extubation time and total dose of remifentanil (P<0.001). Compared with SL group, periumbilical mechanical pain thresholds 6 h and 24 h after surgery significantly decreased in SH group (P<0.05), and the visual analog scale (VAS) scores significantly increased 30 min, 2 h and 6 h after surgery (P<0.05). Compared with SH group, periumbilical mechanical thresholds 6 h and 24 h after surgery were significantly higher in PH group (P<0.05), and VAS scores 30 min, 2 h and 6 h after surgery were significantly lower (P<0.05). PH group first used patient-controlled intravenous analgesia pump significantly later than SL group did (P<0.05). The total consumptions of sufentanil in PH and SL groups were significantly lower than that of SH group (P<0.05). The incidence rates of bradycardia and postoperative chill in PH and SH groups were significantly higher than those of SL group (P<0.05). Anesthesia by infusion of high-dose remifentanil plus sevoflurane caused postoperative hyperalgesia which was relieved through intravenous anesthesia with propofol.