PAIN®最新文献

Abstract: The high failure rate in translating novel analgesics into the clinic has highlighted the need for more translatable biomarkers of analgesic target engagement. The N13 component of spinal somatosensory evoked potential (SEP) has been proposed as a biomarker of spinal nociceptive processing in humans, but it is not known whether this can be back translated into rodents. Tapentadol, lacosamide, and pregabalin were used as pharmacological probes to assess the sensitivity of spinal SEPs to drug action. In anaesthetised, naïve rats (n = 44), a multielectrode silicon probe was inserted into the L4 spinal cord to record SEPs from the dorsal horn after electrical stimulation of the sciatic nerve. At baseline, the N1 component (rodent equivalent of the human N13) had an amplitude of 1.33 ± 0.07 mV at a latency of 4.6 ± 0.2 milliseconds after low-intensity stimulation (average 0.32 mA), with an intensity-dependent amplitude increase into the noxious range (0.4-3.2 mA). The N1 amplitude was significantly reduced by 10 mg/kg tapentadol (40.2 ± 12.5% vs vehicle 96.2 ± 8.0%) and 30 mg/kg lacosamide (46.3 ± 20.9% lacosamide vs vehicle 115 ± 5.9%) at 60 minutes after intraperitoneal administration. Tapentadol also reduced the N1 amplitude in the noxious range. Lacosamide increased the stimulus current required to evoke the half maximal N1 response (EC50), without reducing the maximum N1 amplitude in the noxious range. Pregabalin (at any dose up to 30 mg/kg) did not modulate the N1 amplitude. These results show that the spinal N1 is differentially modulated in a way that reflects distinct mechanisms of analgesic action consistent with it being a translatable biomarker of target engagement.

Abstract: Musculoskeletal pain, particularly low back and neck pain, is associated with maladaptive changes in spinal motor behaviour (SMB). Psychological factors such as pain-related fear play a role in driving these adaptations. While previous research found weak associations between general psychological measures and SMB, task-specific measures may provide more precise insights into movement avoidance. This systematic review and meta-analysis aimed to compare the relative associations of general and task-specific pain-related fear measures with SMB. Following PRISMA guidelines, we included 13 studies (651 participants) assessing both general (Tampa Scale of Kinesiophobia and Pain Anxiety Symptoms Scale) and task-specific measures alongside objective spinal motor outcomes (eg, amplitude, velocity, muscle activity, coordination, variability). A three-level meta-analytic model revealed a weak but significant association between general measures and SMB (r = 0.12, 95% CI: 0.04-0.21, P = 0.007), whereas task-specific measures showed a stronger association (r = 0.29, 95% CI: 0.18-0.40, P < 0.001). The difference between these correlations (Δr (task-specific - general) = 0.16, 95% CI: 0.04 to 0.27, P = 0.008) was statistically significant, indicating that task-specific measures better capture the relationship between perceived fear and movement alterations. Despite methodological heterogeneity, our findings highlight the importance of task-specific assessments in understanding motor impairments associated with pain-related fear. These results support the integration of task-specific evaluations in clinical and research settings. To further elucidate the mechanisms linking psychological factors to SMB, future studies should use longitudinal designs, improve the contextual validity of the motor tasks studied, and explore new approaches of movement analysis.

Abstract: This study aims to identify predictors of success in treating chronic pain patients with full agonist opioids by analyzing harmonized individual patient data from 5594 participants in 9 enriched enrollment randomized withdrawal clinical trials available in the Food and Drug Administration data repository. We analyzed both the participants' success with titration and continued success in the 84-day maintenance phases after randomization for those maintained on the drug. We used the full data set to assess participant demographics and subsets of data containing participant reported outcomes at baseline. Participants had an average age of 51, with 55% female participants and 66% non-Hispanic white. No clinically relevant differences were observed between participants who failed titration or those who continued on full agonists through the maintenance phase. Prediction models were developed using mixed effects logistic regression and generalized linear mixed models, with the study as a random effect to account for inter-study differences. Despite large numbers, the analysis did not reveal clinically useful prediction models for either the titration or maintenance phase; however, higher initial pain scores were modest predictors of poorer outcomes. No patient-reported outcome measures were predictive of responses to therapy. The study's limitations include its volunteer-based sample and the exclusion criteria, although excluding patients with opioid use disorder or serious psychological conditions are similar to those used in clinical care. As no strong predictive factors for successful treatment were identified, the decision to use opioids to treat chronic pain requires careful clinical judgment and close monitoring.

Abstract: Astrocytes are key players in chronic pain, driving maladaptive changes in neuronal circuits. Yet, their influence on acute nociception-the body's first line of defense against harmful stimuli-remains poorly understood. Using chemogenetic tools to mimic endogenous astrocytic G-protein-coupled receptor-mediated signaling, we reveal that astrocytes induce bidirectional plasticity at nociceptive synapses in the dorsal horn. Depending on the state of these synapses and on concurrent afferent input, astrocytes can either suppress nociceptive transmission by enhancing glycinergic tone, or amplify synaptic strength at C-fiber synapses through interactions with microglia. This dynamic regulation expands the acute computational capacity of spinal nociceptive networks, enabling precise and adaptive responses to noxious stimuli on a short time scale. Our findings challenge the traditional view of astrocytes as passive supporters of neuronal activity and establish them as active regulators of spinal plasticity, integrating sensory information and network states to shape pain perception in real time.

Abstract: Pain in pediatric-onset spinal cord injury (SCI) has an unknown prevalence and genetic basis. Cold hyperesthesia is also a key sensory sign in adults with SCI pain. This hypothesis-driven observational and genetic-phenotype study assessed transient receptor potential ankyrin 1 (TRPA1) gene single-nucleotide polymorphism (SNP) clusters rs920829, rs11988795, and rs13255063 as factors associated with pediatric-onset SCI pain. Sixty-six individuals (12.5 ± 0.1 years; 51.5% women) with pediatric-onset SCI (5.2 ± 0.1 years) were evaluated with the International SCI Pain Data Set, Child Pain Anxiety Symptoms Scale, Pain-Catastrophizing Questionnaire, dynamic quantitative sensory testing, and the home-based cold pressor test. Single-nucleotide polymorphisms were identified by melting analysis of DNA amplification with real-time fluorescence polymerase chain reaction. Spinal cord injury pain prevalence, as a cohort percentage, was 50.0% (n = 33), with both nociceptive (n = 25, 37.9%) and probable neuropathic pain (NP, n = 13, 19.7%) present. Case-control analysis revealed that the rs11988795 AG genotype was associated with increased likelihood of any pain (odds ratio [OR] 2.83, 1.02-7.91, P = 0.047), nociceptive pain (OR 3.39, 1.13-10.19, P = 0.029), and NP (OR 5.33, 1.09-25.98, P = 0.038). Both decreased (OR 0.24, 0.08-0.79, P = 0.018) and increased likelihood (OR 3.85, 1.23-12.10, P = 0.021) of musculoskeletal pain were associated with the rs11988795 GG/AG genotype, respectively. Candidate TRPA1 SNPs are also associated with cold hyperesthesia, cold pain, catastrophizing, and anxiety. Both nociceptive and NP pain were present in the cohort, with the TRPA1 rs11988795 and rs13255063 SNPs significantly associated with the likelihood of SCI pain. Further validation of TRPA1 SNPs in a larger pediatric-onset SCI cohort may advance our understanding of the underlying pathophysiology, improve prognosis, and reveal potential targets for future therapeutic exploration.