Engineering a multicompartment in vitro model for dorsal root ganglia phenotypic assessment.

Despite the significant global prevalence of chronic pain, current methods to identify pain therapeutics often fail translation to the clinic. Phenotypic screening platforms rely on modeling and assessing key pathologies relevant to chronic pain, improving predictive capability. Patients with chronic pain often present with sensitization of primary sensory neurons (that extend from dorsal root ganglia [DRG]). During neuronal sensitization, painful nociceptors display lowered stimulation thresholds. To model neuronal excitability, it is necessary to maintain three key anatomical features of DRGs to have a physiologically relevant platform: (1) isolation between DRG cell bodies and neurons, (2) 3D platform to preserve cell-cell and cell-matrix interactions, and (3) presence of native non-neuronal support cells, including Schwann cells and satellite glial cells. Currently, no culture platforms maintain the three anatomical features of DRGs. Herein, we demonstrate an engineered 3D multicompartment device that isolates DRG cell bodies and neurites and maintains native support cells. We observed neurite growth into isolated compartments from the DRG using two formulations of collagen, hyaluronic acid, and laminin-based hydrogels. Further, we characterized the rheological, gelation and diffusivity properties of the two hydrogel formulations and found the mechanical properties mimic native neuronal tissue. Importantly, we successfully limited fluidic diffusion between the DRG and neurite compartment for up to 72 h, suggesting physiological relevance. Lastly, we developed a platform with the capability of phenotypic assessment of neuronal excitability using calcium imaging. Ultimately, our culture platform can screen neuronal excitability, providing a more translational and predictive system to identify novel pain therapeutics to treat chronic pain.

Cannabis-based medicines for chronic pain management: current and future prospects.

PURPOSE OF REVIEW: The medicinal use of cannabis has recently become the focus of much medical, as well as political, attention. This reality of growing use but limited evidence creates unique dilemmas for the prescribing clinician. The purpose of this review is to explore current evidence and gaps in knowledge and offer some practical considerations. RECENT FINDINGS: There is robust preclinical data regarding the relevance of the endocannabinoid system to many pain-relevant processes. However, evidence to support cannabis-based medicines clinical use is still lacking. The best evidence to date is in managing neuropathic pain, although whether effects are clinically significant remains undetermined. However, the safety profile of cannabinoids seems favorable, especially by comparison to other medications used for pain control. SUMMARY: The endocannabinoid system is undoubtedly a new and exciting pharmaceutical target for chronic pain management, but transition from preclinical to clinical studies has so far proved difficult. Although it is reasonable to consider cannabinoids for otherwise unresponsive pain, care should be taken in frail clinical populations. As this has become a socioeconomic and political issue in which agendas often take precedence over due diligence, there is a pressing need for unbiased empirical data and high quality evidence to better inform prescribers and patients.

Assessment of Chronic Pain: Domains, Methods, and Mechanisms.

UNLABELLED: Accurate classification of chronic pain conditions requires reliable and valid pain assessment. Moreover, pain assessment serves several additional functions, including documenting the severity of the pain condition, tracking the longitudinal course of pain, and providing mechanistic information. Thorough pain assessment must address multiple domains of pain, including the sensory and affective qualities of pain, temporal dimensions of pain, and the location and bodily distribution of pain. Where possible, pain assessment should also incorporate methods to identify pathophysiological mechanisms underlying the pain. This article discusses assessment of chronic pain, including approaches available for assessing multiple pain domains and for addressing pathophysiological mechanisms. We conclude with recommendations for optimal pain assessment. PERSPECTIVE: Pain assessment is a critical prerequisite for accurate pain classification. This article describes important features of pain that should be assessed, and discusses methods that can be used to assess the features and identify pathophysiological mechanisms contributing to pain.

Trunk Muscle Size and Composition Assessment in Older Adults with Chronic Low Back Pain: An Intra-Examiner and Inter-Examiner Reliability Study.

OBJECTIVE: To evaluate intra- and inter-examiner reliability for the assessment of relative cross-sectional area, muscle-to-fat infiltration indices, and relative muscle cross-sectional area, i.e., total cross-sectional area minus intramuscular fat, from T1-weighted magnetic resonance images obtained in older adults with chronic low back pain. DESIGN: Reliability study. SUBJECTS: n = 13 (69.3 ± 8.2 years old) METHODS: After lumbar magnetic resonance imaging, two examiners produced relative cross-sectional area measurements of multifidi, erector spinae, psoas, and quadratus lumborum by tracing regions of interest just inside fascial borders. Pixel-intensity summaries were used to determine muscle-to-fat infiltration indices; relative muscle cross-sectional area was calculated. Intraclass correlation coefficients were used to estimate intra- and inter-examiner reliability; standard error of measurement was calculated. RESULTS: Intra-examiner intraclass correlation coefficient point estimates for relative cross-sectional area, muscle-to-fat infiltration indices, and relative muscle cross-sectional area were excellent for multifidi and erector spinae across levels L2-L5 (ICC = 0.77-0.99). At L3, intra-examiner reliability was excellent for relative cross-sectional area, muscle-to-fat infiltration indices, and relative muscle cross-sectional area for both psoas and quadratus lumborum (ICC = 0.81-0.99). Inter-examiner intraclass correlation coefficients ranged from poor to excellent for relative cross-sectional area, muscle-to-fat infiltration indices, and relative muscle cross-sectional area. CONCLUSIONS: Assessment of relative cross-sectional area, muscle-to-fat infiltration indices, and relative muscle cross-sectional area in older adults with chronic low back pain can be reliably determined by one examiner from T1-weighted images. Such assessments provide valuable information, as muscle-to-fat infiltration indices and relative muscle cross-sectional area indicate that a substantial amount of relative cross-sectional area may be magnetic resonance-visible intramuscular fat in older adults with chronic low back pain.

MRI assessment of paraspinal muscles in patients with acute and chronic unilateral low back pain.

OBJECTIVE: To investigate the changes in paraspinal muscle cross-sectional area (CSA) and composition, using the digital data from lumbar spine MRIs of patients with acute and chronic low back pain (LBP). METHODS: In total, 178 patients with unilateral LBP who had lumbar MRI examination were recruited. The data were obtained by a retrospective documentation audit. The CSAs and mean signal intensities of the bilateral paraspinal muscles [psoas major (PM), quadratus lumborum, multifidus (MF) and erector spinae (ES)] were measured, and the percentage of fat infiltration was calculated. The data between the painful side and non-painful side were compared, and between-group comparisons were tested. 42 patients with chronic unilateral LBP could indicate the problem level, and the CSA and mean signal intensity of the MF muscle were analysed at the problem level, and one vertebral above and one vertebral level below the problem level. RESULTS: The CSAs of the PM and ES muscles were significantly decreased in the acute LBP group, while in the chronic LBP group, significant reduction in CSA was found in the MF and ES muscles on the painful side compared with the non-painful side. The mean signal intensity and fat content of the ES muscle on the painful side in the chronic LBP group was significantly higher than that on the painful side in the acute LBP group. The significant decrease of CSA in the MF muscle was found at multiple levels on the painful side. CONCLUSION: The present findings show that there is selective ipsilateral atrophy of paraspinal muscles, specific to the symptomatic side, in patients with acute and chronic LBP. The reduction of the muscle CSA and increased fatty infiltration occurred synchronously, and the extent of change is significantly greater in chronic LBP in the ES muscle. Atrophy of the MF muscle appears to be at multiple levels but side specific in relation to symptoms in patients with chronic LBP, and the decreased muscle CSA may occur prior to fatty infiltration. ADVANCES IN KNOWLEDGE: There are specific paraspinal muscles undergoing atrophy and fatty infiltration in patients with acute and chronic LBP on the symptomatic side. The CSA of the MF muscle decreased at multiple levels on the symptomatic side in patients with chronic unilateral LBP, which may occur prior to fatty infiltration.

White matter hyperintensity burden and disability in older adults: is chronic pain a contributor?

OBJECTIVE: To primarily explore differences in global and regional white matter hyperintensities (WMH) in older adults with self-reported disabling and nondisabling chronic low back pain (CLBP) and to examine the association of WMH with gait speed in all participants with CLBP. To secondarily compare WMH of the participants with CLBP with the pain-free controls. DESIGN: A cross-sectional, case-control study. SETTING: University of Pittsburgh. PARTICIPANTS: Twenty-four community-dwelling older adults: 8 with self-reported disabling CLBP, 8 with nondisabling CLBP, and 8 were pain-free. Exclusions were psychiatric or neurologic disorders (either central or peripheral), substance abuse, opioid use, or diabetes mellitus. METHODS: All participants underwent structural brain magnetic resonance imaging, and all participants with CLBP underwent the 4-m walk test. MAIN OUTCOME MEASUREMENTS: All the participants were assessed for both global and regional WMH by using an automated localization and segmentation method, and gait speed of participants with CLBP. RESULTS: The disabled group demonstrated statistically significant regional WMH in a number of left hemispheric tracts: anterior thalamic radiation (P = .0391), lower cingulate (P = .0336), inferior longitudinal fasciculus (P = .0367), superior longitudinal fasciculus (P = .0011), and the superior longitudinal fasciculus branch to the temporal lobe (P = .0072). Also, there was a statistically significant negative association (rs = -0.57; P = .0225) between the left lower cingulate WMH and the gait speed in all the participants with CLBP. There was a statistical difference in global WMH burden (P = .0014) and nearly all regional tracts (both left and right hemispheres) when comparing CLBP with pain-free participants. CONCLUSIONS: Our findings suggest that WMH is associated with, and hence, may be accelerated by chronic pain manifesting as perceived disability, given the self-reported disabled CLBP patients had the greatest burden, and the pain free the least, and manifesting as measurable disability, given increasing WMH was associated with decreasing gait speed in all chronic pain participants.