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Chronic knee pain (CKP) is a common pain complaint in older adults that is often associated with disability. This study investigated the relationship between 2 components of subjective well-being (depressive symptoms and life satisfaction) and CKP phenotypes based on the presence of knee disability.
Neuropathic pain (NP) is a refractory and long‑lasting disease caused mostly by peripheral nerve injury. Currently, the mechanism of NP is yet to be elucidated. Intracellular calcium homeostasis is critical for some physiological functions, including the occurrence of NP. NCKX2, encoded by the solute carrier family 4 member 2 (SLC24A2) gene, is an important K+‑dependent Na+‑Ca2+ exchanger that mediates Ca2+ extrusion. The role of NCKX2 in the development of NP is unknown. For this purpose, a sciatic nerve chronic constriction injury (CCI) model was established and it was revealed that the expression levels of SLC24A2 and its encoded protein NCKX2 were both downregulated in the posterior horn of the spinal cord. Overexpression of SLC24A2 reduced both mechanical and thermal hyperalgesia and decreased the expression of inflammatory cytokines [interleukin (IL)‑1β, IL‑6 and tumor necrosis factor‑α] in CCI rats. Using bioinformatics analyses, luciferase reporter assays, and a series of behavioral tests, it was demonstrated that the decrease in SLC24A2 after CCI treatment was directly regulated by increased microRNA (miR)‑135a‑5p in the spinal cord. Moreover, the effects of miR‑135a‑5p on NP were SLC24A2‑dependent. In conclusion, the present results highlighted the suppressive role of NCKX2 in NP, which is mainly regulated by miR‑135a‑5p and mediates the release of inflammatory cytokines in the dorsal horn of the spinal cord. These findings deepen our understanding of the development of NP and provide novel candidates for NP treatment.
Millions of people in the United States are affected by chronic pain, and the financial cost of pain treatment is weighing on the healthcare system. In some cases, current pharmacological treatments may do more harm than good, as with the United States opioid crisis. Direct electrical stimulation of the brain is one potential non-pharmacological treatment with a long history of investigation. Yet brain stimulation has been far less successful than peripheral or spinal cord stimulation, perhaps because of our limited understanding of the neural circuits involved in pain perception. In this paper, we review the history of using electrical stimulation of the brain to treat pain, as well as contemporary studies identifying the structures involved in pain networks, such as the thalamus, insula, and anterior cingulate. We propose that the thermal grill illusion, an experimental pain model, can facilitate further investigation of these structures. Pairing this model with intracranial recording will provide insight toward disentangling the neural correlates from the described anatomic areas. Finally, the possibility of altering pain perception with brain stimulation in these regions could be highly informative for the development of novel brain stimulation therapies for chronic pain.
Pain is a growing public health issue worldwide, but there is limited population-based evidence in low- and middle-income country settings. Using nationwide Indonesian Family Life Survey (IFLS) data in 2007 and 2014, this research sets out to investigate the associations between changes in pain status between two time points and its impact on functional health outcomes among middle-aged and older adults in Indonesia. Analyses focused on 7936 adults aged 50 years and older in 2014 who responded to both waves. Functional health was assessed using a composite score of functional limitations (range 20-100), representing difficulty in performing activities of daily living, and grip strength (kilograms). Multivariate linear regression models were used to analyse associations between pain measured in 2007 and 2014 and functional health in 2014. Severe pain in the latest wave of IFLS was associated with older age, female, lower education, having chronic conditions or depressive symptoms. Notably, those who reported 'low-medium' pain in 2007 and 'severe' pain in 2014 belonged to the most vulnerable group with worst functional health outcomes (4.96 points higher limitation scores and 1.17 kg weaker average grip strength). Findings have implications for public health policy in monitoring and management of pain including related co-morbidities as an increasingly critical component of population ageing.
Pain neuroscience education (PNE) is an approach used in the management of chronic musculoskeletal pain (CMP). Previous reviews on PNE and other pain interventions, have focussed on mean treatment effects, but in the context of "precision medicine", any inter-individual differences in treatment response are also important to quantify. If inter-individual differences are present, and predictors identified, PNE could be tailored to certain people for optimising effectiveness. Such heterogeneity can be quantified using recently-formulated approaches for comparing the response variance between the treatment and control groups. Therefore, we conducted a systematic review and meta-analysis on the extracted standard deviations of baseline-to-follow up change to quantify the inter-individual variation in pain, disability and psychosocial outcomes in response to PNE. Electronic databases were searched between 01/01/2002 and 14/06/2018. The review included five randomised controlled trials (n=428) in which disability outcomes were reported. Using a random effects meta-analysis, the pooled SD (95% CI) for control group-adjusted response heterogeneity to PNE was 7.36 units /100 (95% CI: -3.93 to 11.12). The 95% prediction interval for this response heterogeneity SD was wide (-10.20 to 14.57 units /100). The control group-adjusted proportion of "responders" in the population who would be estimated to exceed a clinically important change of 10/100 ranged from 18-45%. Therefore, when baseline-to-follow up random variability in disability is taken into account (informed by the control arm), there is currently insufficient evidence for the notion of clinically important inter-individual differences in disability responses to PNE in people with CMP. The protocol was published on PROSPERO (CRD42017068436). PERSPECTIVE: We bring a novel method to pain science for calculating inter-individual differences in response to a treatment. This is conducted within the context of a systematic review and meta-analysis on PNE. We highlight how using erroneous methods for calculating inter-individual differences can drastically change conclusions when compared to appropriate methods.
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).
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.
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.
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.
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.