- Clinical and Radiographic Predictors for Unsalvageable Labral Tear at the Time of Initial Hip Arthroscopic Management for Femoroacetabular Impingement. [Journal Article]
- AJAm J Sports Med 2019 Jun 24; :363546519856018
- CONCLUSIONS: Age ≥45 years, body mass index ≥23.1 kg/m2, and vertical center anterior angle ≥36° are risk factors for unsalvageable labral tear at initial hip arthroscopic surgery for patients with FAI.
- Molecular mechanisms of human P2X3 receptor channel activation and modulation by divalent cation bound ATP. [Journal Article]
- EElife 2019 Jun 24; 8
- P2X3 receptor channels expressed in sensory neurons are activated by extracellular ATP and serve important roles in nociception and sensory hypersensitization, making them attractive therapeutic targ…
P2X3 receptor channels expressed in sensory neurons are activated by extracellular ATP and serve important roles in nociception and sensory hypersensitization, making them attractive therapeutic targets. Although several P2X3 structures are known, it is unclear how physiologically abundant Ca2+-ATP and Mg2+-ATP activate the receptor, or how divalent cations regulate channel function. We used structural, computational and functional approaches to show that a crucial acidic chamber near the nucleotide-binding pocket in human P2X3 receptors accommodates divalent ions in two distinct modes in the absence and presence of nucleotide. The unusual engagement between the receptor, divalent ion and the γ-phosphate of ATP enables channel activation by ATP-divalent complex, cooperatively stabilizes the nucleotide on the receptor to slow ATP unbinding and recovery from desensitization, a key mechanism for limiting channel activity. These findings reveal how P2X3 receptors recognize and are activated by divalent-bound ATP, aiding future physiological investigations and drug development.
- Prolactin receptor expression in mouse dorsal root ganglia neuronal subtypes is sex-dependent. [Journal Article]
- JNJ Neuroendocrinol 2019 Jun 24; :e12759
- Sensory neurons exhibit sex-dependent responsiveness to prolactin (PRL). This could contribute to sexual dimorphism in pathological pain conditions. The aim of this study is to elucidate mechanisms u…
Sensory neurons exhibit sex-dependent responsiveness to prolactin (PRL). This could contribute to sexual dimorphism in pathological pain conditions. The aim of this study is to elucidate mechanisms underlying sex-dependent PRL sensitivity in sensory neurons. Quantitative RT-PCR show that prolactin receptor (Prlr) long and short isoform mRNAs are expressed at comparable levels in female and male mouse dorsal root ganglia (DRG). In Prlrcre/+ ;Rosa26LSL - tDT omato/+ reporter mice, percentages of Prlr+ sensory neurons in female and male DRG are also similar. Characterization of Prlr+ DRG neurons using immunohistochemistry and electrophysiology revealed that Prlr+ DRG neurons are mainly peptidergic nociceptors in females and males. However, sensory neuron type-dependent expression of Prlr is sex dimorphic. Thus, Prlr+ populations fell into three small- and two medium-large-sized sensory neuronal groups. Prlr+ DRG neurons are predominantly medium-large sized in males and are proportionally more comprised of small-sized sensory neurons in females. Specifically, Prlr+ /IB4+ /CGRP+ neurons are 4-5-fold higher in numbers in female DRG. In contrast, Prlr+ /IB4- /CGRP+ /5HT3a+ /NPYR2- are predominant in male DRG. Prlr+ /IB4- /CGRP- , Prlr+ /IB4- /CGRP+ and Prlr+ /IB4- /CGRP+ /NPYR2+ neurons are evenly encountered in female and male DRG. These differences were confirmed using an independently generated single-cell sequencing dataset. Overall, we propose a novel mechanism whereby sensory neuron type-dependent expression of Prlr could explain the unique sex dimorphism in responsiveness of nociceptors to PRL. This article is protected by copyright. All rights reserved.
- Potential of dehydroepiandrosterone in modulating osteoarthritis-related pain. [Review]
- SSteroids 2019 Jun 20; :108433
- Osteoarthritis (OA) is the most common form of degenerative arthropathy, and the primary symptom is chronic joint pain. Dehydroepiandrosterone (DHEA) exerts a chondroprotective effect against OA and …
Osteoarthritis (OA) is the most common form of degenerative arthropathy, and the primary symptom is chronic joint pain. Dehydroepiandrosterone (DHEA) exerts a chondroprotective effect against OA and has been reported to have potent structure-modifying effects on osteoarthritic cartilage, thereby attenuating disease progression. However, the ability of DHEA to modulate OA-related pain has not yet been verified. Recent evidence suggests that there may be a link between the pharmacological effects of DHEA and pain generation. For example, DHEA synthesized in the adrenal gland interferes directly with nerve growth factor (NGF) receptors, a major biochemical contributor to peripheral hypersensitivity. Similarly, endogenous DHEA produced in the spinal cord exerts a regulatory effect on nociception in neuropathic rats. In this short review, we discuss recent studies concerning crucial signalling cascades and molecular mechanisms involved in pain generation as well as the potential link between DHEA activity and nociception. Particular attention is given to the putative molecular mechanisms underlying the favourable efficacy of DHEA against pain generation. Elucidating the molecular mechanisms of DHEA against osteoarthritic pain may pave the way for the discovery and development of novel anti-OA drugs, as effective drugs for OA treatment are not currently available.
- Involvement of Endothelin Receptors in Peripheral Sensory Neuropathy Induced by Oxaliplatin in Mice. [Journal Article]
- NRNeurotox Res 2019 Jun 21
- The aim of this study was to evaluate the participation of the endothelin ETA and ETB receptors and the effects of bosentan in oxaliplatin-induced peripheral sensory neuropathy (OIN) in mice. Adult m…
The aim of this study was to evaluate the participation of the endothelin ETA and ETB receptors and the effects of bosentan in oxaliplatin-induced peripheral sensory neuropathy (OIN) in mice. Adult male Swiss mice received 1 mg/kg of oxaliplatin intravenously, twice a week for 5 weeks. Dorsal root ganglia (DRG) and spinal cords were removed for evaluation of the endothelin ETA and ETB receptor expression. Afterwards, selective (BQ-123 and BQ-788; 10 nmol in 30 μL, intraplantarly) and non-selective (bosentan, 100 mg/kg, orally) antagonists were administered in order to evaluate the involvement of the endothelin receptors in OIN. Mechanical and thermal nociception tests were performed once a week for 56 days. Oxaliplatin induced mechanical and thermal hypersensitivity and increased the endothelin ETA receptor expression in both the DRG and spinal cord (P < 0.05). Endothelin ETB receptor expression was increased in the DRG (P < 0.05) but not in the spinal cord. Both endothelin ETA and ETB receptor selective antagonists partially prevented mechanical hyperalgesia in mice with OIN (P < 0.05). Moreover, bosentan prevented mechanical and thermal hypersensitivity in oxaliplatin-treated mice (P < 0.05). In conclusion, both endothelin ETA and ETB receptors seem to be involved in the OIN in mice and they should be considered possible targets for the management of this clinical feature.
- OnabotulinumtoxinA Reduces Temporal Pain Processing at Spinal Level in Patients with Lower Limb Spasticity. [Journal Article]
- TToxins (Basel) 2019 Jun 20; 11(6)
- Spasticity is a muscle tone disorder associated with different neurological conditions. Spasticity could be associated with pain, high disability, poor functional recovery, and reduced quality of lif…
Spasticity is a muscle tone disorder associated with different neurological conditions. Spasticity could be associated with pain, high disability, poor functional recovery, and reduced quality of life. Botulinum neurotoxin type A (BoNT-A) is considered a first-line treatment for spasticity and, more recently, it also represents a therapeutic option for various chronic pain conditions. In this open label study, we aim to evaluate the effect of the BoNT-A on the spinal nociception in patients affected by spasticity of the lower limbs with associated pain with predominantly neuropathic features. Ten patients with stroke, 10 with multiple sclerosis and 5 with spinal cord injury were enrolled in the study. They were tested with clinical scales (neuropathic pain scale inventory (NPSI), numerical rating scale (NRS), modified Ashworth scale (MAS) and with the nociceptive withdrawal reflex at lower limbs to explore the spinal temporal summation threshold at baseline and 30 day after BoNT-A injection. OnabotulinumtoxinA (50 to 200 units per site) was injected in the lower limb muscles according to the distribution of spasticity. No significant differences were found at baseline for neurophysiological features across groups. After the BoNT-A injection, we recorded a significant reduction in MAS and NRS scores. Regarding the neurophysiological parameters, we described a significant increase in the temporal summation threshold after the BoNT-A injection. Our data supports the hypothesis that peripherally injected OnabotulinumtoxinA modulates the excitability of spinal cord nociceptive pathways. This activity may take place irrespective of the effect of the drug on spasticity.
- Naloxone prolongs abdominal constriction writhing-like behavior in a zebrafish-based pain model. [Journal Article]
- NLNeurosci Lett 2019 Jun 17; :134336
- The ability to detect noxious stimuli is essential to survival. However, pathological pain is maladaptive and severely debilitating. Endogenous and exogenous opioids modulate pain responses via opioi…
The ability to detect noxious stimuli is essential to survival. However, pathological pain is maladaptive and severely debilitating. Endogenous and exogenous opioids modulate pain responses via opioid receptors, reducing pain sensibility. Due to the high genetic and physiological similarities to rodents and humans, the zebrafish is a valuable tool to assess pain responses and the underlying mechanisms involved in nociception. Although morphine attenuates pain-like responses of zebrafish, there are no data showing if the antagonism of opioid receptors prolongs pain duration in the absence of an exogenous opioid. Here, we investigated whether a common opioid antagonist naloxone affects the abdominal constriction writhing-like response, recently characterized as a zebrafish-based pain behavior. Animals were injected intraperitoneally with acetic acid (5.0%), naloxone (1.25 mg/kg; 2.5 mg/kg; 5.0 mg/kg) or acetic acid with naloxone to investigate the changes in their body curvature for 1 h. Acetic acid elicited a robust pain-like response in zebrafish, as assessed by aberrant abdominal body curvature, while no effects were observed following PBS injection. Although naloxone alone did not alter the frequency and duration of this behavior, it dose-dependently prolonged acetic acid-induced abdominal curvature response. Besides reinforcing the use of the abdominal writhing-like phenotype as a behavioral endpoint to measure acute pain responses in zebrafish models, our novel data suggest a putative role of endogenous opioids in modulating the recovery from pain stimulation in zebrafish.
- Drosophila melanogaster foraging regulates a nociceptive-like escape behavior through a developmentally plastic sensory circuit. [Journal Article]
- PNProc Natl Acad Sci U S A 2019 Jun 18
- Painful or threatening experiences trigger escape responses that are guided by nociceptive neuronal circuitry. Although some components of this circuitry are known and conserved across animals, how t…
Painful or threatening experiences trigger escape responses that are guided by nociceptive neuronal circuitry. Although some components of this circuitry are known and conserved across animals, how this circuitry is regulated at the genetic and developmental levels is mostly unknown. To escape noxious stimuli, such as parasitoid wasp attacks, Drosophila melanogaster larvae generate a curling and rolling response. Rover and sitter allelic variants of the Drosophila foraging (for) gene differ in parasitoid wasp susceptibility, suggesting a link between for and nociception. By optogenetically activating cells associated with each of for's promoters (pr1-pr4), we show that pr1 cells regulate larval escape behavior. In accordance with rover and sitter differences in parasitoid wasp susceptibility, we found that rovers have higher pr1 expression and increased sensitivity to nociception relative to sitters. The for null mutants display impaired responses to thermal nociception, which are rescued by restoring for expression in pr1 cells. Conversely, knockdown of for in pr1 cells phenocopies the for null mutant. To gain insight into the circuitry underlying this response, we used an intersectional approach and activity-dependent GFP reconstitution across synaptic partners (GRASP) to show that pr1 cells in the ventral nerve cord (VNC) are required for the nociceptive response, and that multidendritic sensory nociceptive neurons synapse onto pr1 neurons in the VNC. Finally, we show that activation of the pr1 circuit during development suppresses the escape response. Our data demonstrate a role of for in larval nociceptive behavior. This function is specific to for pr1 neurons in the VNC, guiding a developmentally plastic escape response circuit.
- A distinct structural mechanism underlies TRPV1 activation by piperine. [Journal Article]
- BBBiochem Biophys Res Commun 2019 Jun 15
- Piperine, the principle pungent compound in black peppers, is known to activate the capsaicin receptor TRPV1 ion channel. How piperine interacts with the channel protein, however, remains unclear. He…
Piperine, the principle pungent compound in black peppers, is known to activate the capsaicin receptor TRPV1 ion channel. How piperine interacts with the channel protein, however, remains unclear. Here we show that piperine binds to the same ligand-binding pocket as capsaicin but in different poses. There was no detectable detrimental effect when T551 and E571, two major sites known to form hydrogen bond with capsaicin, were mutated to a hydrophobic amino acid. Computational structural modeling suggested that piperine makes interactions with multiple amino acids within the ligand binding pocket, including T671 on the pore-forming S6 segment. Mutations of this residue could substantially reduce or even eliminate piperine-induced activation, confirming that T671 is an important site. Our results suggest that the bound piperine may directly interact with the pore-forming S6 segment to induce channel opening. These findings help to explain why piperine is a weak agonist, and may guide future efforts to develop novel pharmaceutical reagents targeting TRPV1.
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- Prediction of postoperative pain and analgesic requirements using surgical pleth index: a observational study. [Journal Article]
- JCJ Clin Monit Comput 2019 Jun 17
- The aim of this study was to evaluate the performance of surgical pleth index (SPI) measured before arousal from general anaesthesia for prediction of immediate postoperative pain and postoperative o…
The aim of this study was to evaluate the performance of surgical pleth index (SPI) measured before arousal from general anaesthesia for prediction of immediate postoperative pain and postoperative opioid requirement during postoperative 48 h. After obtaining ethical approval and written informed consent, we enrolled 51 patients undergoing liver resection under isoflurane based general anaesthesia using laryngeal mask airway in this prospective observational study. Data relating to SPI values were recorded every 30 s for the last 3 min of surgery (bispectral index < 60 at all times). Postoperative pain intensity was assessed using a 0-10 numerical rating scale (NRS) every 10 min in the recovery room. The relationships between SPI with postoperative pain score and opioid requirement were analysed. A receiver-operating characteristic curve (ROC) was used to evaluate the performance of SPI to predict NRS ≥ 5. SPI value was significantly associated with the highest pain score in the recovery room (r = 0.63, p < 0.001). An SPI value of 60, which showed the highest sensitivity and specificity, was defined post hoc as the cut-off for moderate-severe pain (NRS ≥ 5). When compared the patients who showed SPI value over 60 or not, there was significant difference in the amount of fentanyl consumption during postoperative 48 h (1093 ± 406 µg vs. 766 ± 369 µg, p = 0.014; SPI ≥ 60 vs. SPI < 60). SPI measured before arousal after inhalation anaesthesia was associated with immediate postoperative pain and postoperative opioid consumption.