- Award ID(s):
- 1835000
- NSF-PAR ID:
- 10315568
- Date Published:
- Journal Name:
- Nature Biomedical Engineering
- ISSN:
- 2157-846X
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
More Like this
-
Closed-loop stimulation using a multiregion brain-machine interface has analgesic effects in rodentsPain relief on-demand Chronic pain is a debilitating condition for which there are no effective treatments. The primary somatosensory cortex (S1) and the anterior cingulate cortex (ACC) are involved in decoding pain components, and electrical stimulation of the prefrontal cortex (PFC) has been shown to exert analgesic effects. Here, Sun et al. developed a multiregion brain-machine interface (BMI) able to detect pain from electrical signals in S1 and ACC and provide on-demand PFC stimulation. The BMI was able to accurately detect and treat acute and chronic pain in rats; the analgesic effects were stable over time. The results suggest that BMI approaches might be effective for treating chronic pain of different etiologies.more » « less
-
Abstract Background Native Americans (NAs) are more likely to experience chronic pain than non-Hispanic Whites (NHWs); however, the proximate causes predisposing NAs to chronic pain remain elusive. Likely due to centuries of adversity, discrimination, and marginalization, NAs report greater psychological stress than NHWs, which may place them at risk for sleep problems, a well-established risk factor for chronic pain onset.
Purpose This study examined the effects of psychological stress and sleep problems on subjective and physiological measures of pain processing in NAs and NHWs.
Methods Structural equation modeling was used to determine whether ethnicity (NA or NHW) was associated with psychological stress or sleep problems and whether these variables were related to conditioned pain modulation of pain perception (CPM-pain) and the nociceptive flexion reflex (CPM-NFR), temporal summation of pain (TS-pain) and NFR (TS-NFR), and pain tolerance in a sample of 302 (153 NAs) pain-free participants.
Results NAs experienced more psychological stress (Estimate = 0.027, p = .009) and sleep problems (Estimate = 1.375, p = .015) than NHWs. When controlling for age, sex, physical activity, BMI, and general health, NA ethnicity was no longer related to greater sleep problems. Psychological stress was also related to sleep problems (Estimate = 30.173, p = <.001) and psychological stress promoted sleep problems in NAs (indirect effect = 0.802, p = .014). In turn, sleep problems were associated with greater TS-pain (Estimate = 0.714, p = .004), but not other pain measures.
Conclusions Sleep problems may contribute to chronic pain risk by facilitating pain perception without affecting facilitation of spinal neurons or endogenous inhibition of nociceptive processes. Since psychological stress promoted pain facilitation via enhanced sleep problems, efforts to reduce psychological stress and sleep problems among NAs may improve health outcomes.
-
Endocannabinoids are lipid neuromodulators that are synthesized on demand and primarily signal in a retrograde manner to elicit depression of excitatory and inhibitory synapses. Despite the considerable interest in their potential analgesic effects, there is evidence that endocannabinoids can have both pro-nociceptive and anti-nociceptive effects. The mechanisms contributing to the opposing effects of endocannabinoids in nociception need to be better understood before cannabinoid-based therapies can be effectively utilized to treat pain. Using the medicinal leech, Hirudo verbana , this work investigates whether endocannabinoids modulate tonic inhibition onto non-nociceptive afferents. In voltage clamp recordings, we analyzed changes in the tonic inhibition in pressure-sensitive (P) cells following pre-treatment with endocannabinoids, 2-arachidonoylglycerol (2-AG) or anandamide (AEA). We also tested whether high frequency stimulation (HFS) of nociceptive (N) cells could also modulate tonic inhibition. Both endocannabinoid application and N cell HFS depressed tonic inhibition in the P cell. Depression of tonic inhibition by N cell HFS was blocked by SB 366791 (a TRPV1 inhibitor). SB 366791 also prevented 2-AG-and AEA-induced depression of tonic inhibition. HFS-induced depression was not blocked by tetrahydrolipstatin (THL), which prevents 2-AG synthesis, nor AM 251 (a CB1 receptor inverse agonist). These results illustrate a novel activity-dependent modulation of tonic GABA currents that is mediated by endocannabinoid signaling and is likely to play an important role in sensitization of non-nociceptive afferent pathways.more » « less
-
Abstract Classical target‐based drug screening is low‐throughput, largely subjective, and costly. Phenotypic screening based on in vitro models is increasingly being used to identify candidate compounds that modulate complex cell/tissue functions. Chronic inflammatory nociception, and subsequent chronic pain conditions, affect peripheral sensory neuron activity (e.g., firing of action potentials) through myriad pathways, and remain unaddressed in regard to effective, non‐addictive management/treatment options. Here, a chronic inflammatory nociception model is demonstrated based on induced pluripotent stem cell (iPSC) sensory neurons and glia, co‐cultured on microelectrode arrays (MEAs). iPSC sensory co‐cultures exhibit coordinated spontaneous extracellular action potential (EAP) firing, reaching a stable baseline after ≈27 days in vitro (DIV). Spontaneous and evoked EAP metrics are significantly modulated by 24‐h incubation with tumor necrosis factor‐alpha (TNF‐α), representing an inflammatory phenotype. Compared with positive controls (lidocaine), this model is identified as an “excellent” stand‐alone assay based on a modified Z’ assay quality metric. This model is then used to screen 15 cherry‐picked, off‐label, Food and Drug Administration (FDA)‐approved compounds; 10 of 15 are identified as “hits”. Both hits and “misses” are discussed in turn. In total, this data suggests that iPSC sensory co‐cultures on MEAs may represent a moderate‐to‐high‐throughput assay for drug discovery targeting inflammatory nociception.
-
Mechanical distension beyond a particular threshold evokes visceral pain from distal colon and rectum (colorectum) and thus biomechanics plays a central role in visceral nociception. In this study we focused on the layered structure of the colorectum through the wall thickness and determined the biomechanical properties of layer-separated colorectal tissue. We harvested the distal 30 mm of mouse colorectum and dissected into inner and outer composite layers. The inner composite consists of the mucosa and submucosa while the outer composite includes the muscular layers and serosa. We divided each composite axially into three 10 mm-long segments and conducted biaxial mechanical extension tests and opening-angle measurements for each tissue segment. In addition, we quantified the thickness of the rich collagen network in the submucosa by nonlinear imaging via second harmonic generation (SHG). Our results reveal the inner composite is slightly stiffer in the axial direction while the outer composite is stiffer circumferentially. The stiffness of the inner composite in the axial direction is about twice that in the circumferential direction, consistent with the orientations of collagen fibers in the submucosa approximately ±30 degrees to the axial direction. Submucosal thickness measured by SHG showed no difference from proximal to distal colorectum under load-free condition, which likely contributes to the comparable tension stiffness of the inner composite along the colorectum. This, in turn, strongly indicates the submucosa as the load-bearing structure of the colorectum. This further implies nociceptive roles for the colorectal afferent endings in the submucosa that likely encode tissue-injurious mechanical distension.more » « less