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The main objective of this study was to assess painful memory as well as long-term episodic memory, both in patients with chronic pain (CP) and in asymptomatic participants (AP).
Learn More >Some chronic pain conditions and comorbidities suppress the hypothalamic-pituitary-adrenal (HPA) axis and response to dynamic testing. We measured HPA axis responses to corticotropin-releasing hormone (CRH) administration in relation to chronic pelvic pain and endometriosis. In a cross-sectional study of women (n = 54) with endometriosis-associated chronic pelvic pain (n = 22), chronic pelvic pain alone (n = 12), or healthy volunteers (n = 20), adrenocorticotropic-releasing hormone (ACTH) and cortisol levels were measured at 0, 15, 30, and 45 min after intravenous ovine CRH administration. ACTH and cortisol delta (peak-baseline) and area under the curve (AUC) were compared by study group and assessed for association with race and menstrual and non-menstrual pain severity. HPA axis responses did not differ among the racially diverse groups or in those with pain compared with healthy volunteers. However, when stratified by race, ACTH delta (129.9 ± 130.7 vs. 52.5 ± 66.0 pg/mL; p = 0.003), ACTH AUC (4813 ± 4707 vs. 2290 ± 2900 min*pg/mL; p = 0.013), and cortisol delta (26.3 ± 21.5 vs. 13.2 ± 9.7 μg/mL; p = 0.005) were significantly higher in black (n = 10) than predominately white (non-black) subjects (n = 44; 39/44 white). In analyses among primarily white (non-black) women, greater menstrual pain severity was associated with blunted ACTH delta (p = 0.015) and cortisol delta (p = 0.023), and greater non-menstrual pain severity with blunted cortisol delta (p = 0.017). Neuroendocrine abnormalities in women with chronic pelvic pain may differ by pain manifestations and may vary by race. The higher HPA axis response in black women merits investigation in pelvic pain studies stratified by race. In white (non-black) women experiencing pain, a blunted response was related to pain severity suggesting pain affects women independently of endometriosis lesions.
Learn More >Anti-cancer therapy based on the repeated administration of oxaliplatin is limited by the development of a disabling neuropathic syndrome with detrimental effects on the patient's quality of life. The lack of effective pharmacological approaches calls for the identification of innovative therapeutic strategies based on new targets. We focused our attention on the imidazoline I receptor (I-R) and in particular on the selective I-R agonist 2-(1-([1,1'-biphenyl]-2-yl)propan-2-yl)-4,5-dihydro-1H-imidazole) (carbophenyline). The purpose of this work was the preclinical evaluation of the efficacy of carbophenyline on oxaliplatin-induced neuropathic pain in mice. Carbophenyline, acutely per os administered (0.1-10 mg kg), induced a dose-dependent anti-hyperalgesic effect that was completely blocked by the pre-treatment with the I-R antagonist 3 or the I/α receptor antagonist efaroxan, confirming the I-R-dependent mechanism. Conversely, pre-treatment with the I-R antagonist BU224 did not block the anti-nociceptive effect evoked by carbophenyline. Repeated oral administrations of carbophenyline (1 mg kg) for 14 days, starting from the first day of oxaliplatin injection, counteracted the development of neuropathic pain in all behavioral tests (cold plate, Von Frey, and paw pressure tests) carried out 24 h after the last carbophenyline treatment on days 7 and 14. In the dorsal horn of the spinal cord, carbophenyline significantly decreased the oxaliplatin-induced astrocyte activation detected by immunofluorescence staining by the specific labelling with GFAP antibody. In conclusion, carbophenyline showed anti-neuropathic properties both after acute and chronic treatment with preventive effect against oxaliplatin-induced astrocyte activation in the spinal cord. Therefore, I-R agonists emerge as a new class of candidates for the management of oxaliplatin-induced neuropathic pain.
Learn More >The rostral agranular insular cortex (RAIC) is a relevant structure in nociception. Indeed, recruitment of GABAergic activity in RAIC promotes the disinhibition of the locus coeruleus (LC), which in turn inhibits (by noradrenergic action) the peripheral nociceptive input at the spinal cord level. In this regard, at the cortical level, oxytocin can modulate the GABAergic transmission; consequently, an interaction modulating nociception could exist between oxytocin and GABA at RAIC. Here, we tested in male Wistar rats the effect of oxytocin microinjection into RAIC during an inflammatory (by subcutaneous peripheral injection of formalin) nociceptive input. Oxytocin microinjection produces a diminution of (i) flinches induced by formalin and (ii) spontaneous firing of spinal wide dynamic range cells. The above antinociceptive effect was abolished by microinjection (at RAIC) of (i) L-368,899 (an oxytocin receptor -OTR- antagonist) or by (ii) bicuculline (a preferent GABA receptor blocker), suggesting a GABAergic activation induced by OTR. Since intrathecal injection of an α-adrenoceptor antagonist (BRL 44408) partially reversed the oxytocin effect, a descending noradrenergic antinociception is suggested. Besides, injection of L-368,899 induces a pronociceptive behavioral effect, suggesting a tonic endogenous oxytocin release during inflammatory nociceptive input. Accordingly, we found bilateral projections from the paraventricular nucleus of the hypothalamus (PVN) to RAIC. Some of the PVN-projecting cells are oxytocinergic and destinate GABAergic and OTR-expressing cells inside RAIC. Aside from the direct anatomical link between PVN and RAIC, our findings provide evidence about the role of oxytocinergic mechanisms modulating the pain process at the RAIC level.Oxytocin is a neuropeptide involved in several functions ranging from lactation to social attachment. Over the years, the role of this molecule in pain processing has emerged, showing that at the spinal level, oxytocin blocks pain transmission. The present work suggests that oxytocin also modulates pain at the cortical insular level by favoring cortical GABAergic transmission and activating descending spinal noradrenergic mechanisms. Indeed, we show that the paraventricular hypothalamic nucleus sends direct oxytocinergic projections to the rostral agranular insular cortex on GABAergic and oxytocin receptor expressing neurons. Together, our data support the notion that the oxytocinergic system could act as an orchestrator of pain modulation.
Learn More >Effective treatment of high-impact pain patients is one of the major stated goals of the National Pain Strategy in the United States. Identification of new targets and mechanisms underlying neuropathic pain will be critical in developing new target-specific medications for better neuropathic pain management. We recently discovered that peripheral nerve injury-induced upregulation of an axonal guidance phosphoprotein collapsin response mediator protein 2 (CRMP2) and the N-type voltage-gated calcium (CaV2.2) as well as the NaV1.7 voltage-gated sodium channel, correlates with the development of neuropathic pain. In our previous studies, we found that interfering with the phosphorylation status of CRMP2 is sufficient to confer protection from chronic pain. Here we examined the expression of CRMP2 and CRMP2 phosphorylated by cyclin-dependent kinase 5 (Cdk5, on serine residue 522 (S522)) in sciatic nerve, nerve terminals of the glabrous skin, and in select subpopulations of DRG neurons in the SNI model of neuropathic pain. By enhancing our understanding of the phosphoregulatory status of CRMP2 within DRG subpopulations, we may be in a better position to design novel pharmacological interventions for chronic pain.
Learn More >The transient receptor potential cation channel subfamily V member 3 (TRPV3) channel plays a critical role in skin physiology, and mutations in TRPV3 result in the development of a congenital skin disorder, Olmsted syndrome. Here we describe multiple cryo-electron microscopy structures of human TRPV3 reconstituted into lipid nanodiscs, representing distinct functional states during the gating cycle. The ligand-free, closed conformation reveals well-ordered lipids interacting with the channel and two physical constrictions along the ion-conduction pore involving both the extracellular selectivity filter and intracellular helix bundle crossing. Both the selectivity filter and bundle crossing expand upon activation, accompanied by substantial structural rearrangements at the cytoplasmic intersubunit interface. Transition to the inactivated state involves a secondary structure change of the pore-lining helix, which contains a π-helical segment in the closed and open conformations, but becomes entirely α-helical upon inactivation. Together with electrophysiological characterization, structures of TRPV3 in a lipid membrane environment provide unique insights into channel activation and inactivation mechanisms.
Learn More >Transient receptor potential vanilloid subfamily member 3 (TRPV3) is a temperature-sensitive cation channel. Previous cryo-EM analyses of TRPV3 in detergent micelles or amphipol proposed that the lower gate opens by α-to-π helical transitions of the nearby S6 helix. However, it remains unclear how physiological lipids are involved in the TRPV3 activation. Here we determined the apo state structure of mouse (Mus musculus) TRPV3 in a lipid nanodisc at 3.3 Å resolution. The structure revealed that lipids bound to the pore domain stabilize the selectivity filter in the narrow state, suggesting that the selectivity filter of TRPV3 affects cation permeation. When the lower gate is closed in nanodisc-reconstituted TRPV3, the S6 helix adopts the π-helical conformation without agonist- or heat-sensitization, potentially stabilized by putative intra-subunit hydrogen bonds and lipid binding. Our findings provide insights into the lipid-associated gating mechanism of TRPV3.
Learn More >To understand the changes in functional connectivity between brain areas of potential importance in migraine during different phases of the attack.
Learn More >Chronic pain is consistently associated with the presence of mental health disorders. Although previous research has shown relations between low levels of self-efficacy with chronic pain severity as well as comorbid mental health symptoms, the link between self-efficacy and mental health symptoms in chronic pain is not well understood. This study examined whether pain centrality, the extent to which pain is viewed as central to self-identity, may underlie these associations. Individuals with a diagnosis of chronic pain (N = 89) recruited through MTurkcompleted self-report measures including demographics, self-efficacy, pain centrality, pain severity, depression, and anxiety. Pain severity was associated with higher levels of pain centrality, depression, anxiety, and lower levels of self-efficacy. Path analysis demonstrated pain centrality significantly mediated the relationship between self-efficacy and pain severity, depression, and anxiety. Future studies would benefit from testing whether modifying pain centrality beliefs shift perceptions of control as well as pain and psychological outcomes.
Learn More >Exercise is a core treatment for persistent non-specific low back pain (NSLBP), but results from randomised controlled trials (RCTs) of exercise typically show only small to moderate standardised mean differences (SMDs) compared to non-exercise controls. The choice of primary outcome, and relationship to the specific targets of exercise may influence this. This systematic review aimed to explore whether primary outcomes match the exercise treatment targets used in NSLBP RCTs and the potential impact of matching on SMDs. Included RCTs were conducted with patients with persistent NSLBP, compared exercise to no exercise, with sample sizes >60 per arm. Screening, data extraction and risk of bias assessment were independently undertaken by paired reviewers. Of 19272 initial titles, 27 RCTs were included with 31 treatment targets and 6 primary outcome domains identified. Only 25% of included RCTs had primary outcomes that matched the treatment targets. SMDs of exercise versus comparison arms were observed to be larger in the matched (SMD 0.54 (95% CI 0.23 to 0.85), p=0.0006) compared to the unmatched category (SMD 0.22 (95% CI 0.01, 0.44) p=0.04) but this difference was not statistically significant (p=0.10). These exploratory findings may have implications for future teams developing RCTs of exercise for NSLBP and warrant further investigation in larger datasets. Perspective This review was an exploratory study that investigated the primary outcome and treatment targets used in RCTs of exercise for NSLBP. The SMDs of the matched group were descriptively larger than those of the unmatched group, but further analysis with larger sample sizes is required to have confidence in these results.
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