Molecular Pain最新文献

Sensing cooling temperatures is achieved by primary afferent endings located in the skin and is essential for the survival of animals. TRPM8 channels, primarily expressed in cutaneous C-fibers, have been established as receptors for cooling temperatures, sensing innocuous cooling from the normal skin temperature near 30°C to 17°C, and noxious cooling below 17°C. A cooling sensation is also felt when skin temperatures are first elevated to higher temperatures, for example, noxious heat, and then cool down to the normal skin temperature near 30°C. It is currently not clear what types of cutaneous afferent fibers are involved in sensing the cooling from a high heat to the normal skin temperature. Cutaneous Aβ-fiber low-threshold mechanoreceptors (Aβ-LTMRs) are primarily involved in the sense of touch and are thought to play no role in cooling sensation. In the present study, we conducted the opto-electrophysiological recordings from the skin-nerve preparations made from the hindpaw glabrous skin of Nav1.8-ChR2 transgenic mice. In these transgenic mice, Nav1.8-ChR2-negative Aβ-fiber mechanoreceptors are primarily Aβ-LTMRs, and Nav1.8-ChR2-positive Aβ-fiber mechanoreceptors are mainly high-threshold mechanoreceptors (Aβ-HTMRs). Neither Aβ-LTMRs nor Aβ-HTMRs responded to temperature rising from 30°C to the noxious heat of 43°C. However, a subpopulation of Aβ-LTMRs, but not Aβ-HTMRs, robustly fires action potential impulses in response to the temperature drop from 43°C to 30°C. This finding reveals for the first time that a subpopulation of Aβ-LTMRs senses the cooling for a temperature drop from noxious heat to normal skin temperature.

Long-term effects of lumbar disc herniation treatment on brain function are poorly understood, and it is unclear when surgery should be recommended over non-operative treatment. The overall aim of the present study was to determine potential long-term effects on brain networks among individuals who received either surgical or non-operative treatment for lumbar disc herniation in adolescence. Brain network connectivity was assessed for individuals who received surgical treatment or non-operative treatment, and controls with no history of lumbar disc herniation. Prior to analysis, brain connectivity measures between groups were determined as main outcome, using functional magnetic resonance imaging. On average 12 years after treatment onset, the surgically treated cohort exhibited distinctly different functional brain connectivity, compared with both non-operative treatment and controls. The difference was neither attributed to self-reported pain, nor lumbar spine morphology. The findings suggest that surgical treatment for lumbar disc herniation in adolescence may be associated with a long-term imprint on the functional brain connectome.

Preclinical studies show that vortioxetine displays a robust analgesic activity in models of neuropathic pain. Here, we compared the effect of a 2-week treatment with vortioxetine, duloxetine, amitriptyline, fluoxetine, and paroxetine (all injected i.p. at the daily dose of 10 mg/kg) on mechanical and thermal pain thresholds, risk-taking behaviour and depressive-like behaviour in the streptozotocin (STZ) mouse model of painful diabetic neuropathy. Vortioxetine, duloxetine and amitriptyline reduced mechanical pain in diabetic mice, with vortioxetine displaying the greatest efficacy. In contrast, paroxetine and fluoxetine were inactive. Vortioxetine, duloxetine, amitriptyline and paroxetine were also effective in enhancing thermal pain thresholds in diabetic mice. Induction of diabetes did not affect risk-taking behaviour in the light-dark box test but enhanced depressive-like behaviour in the tail suspension test. All antidepressants, with the exception of amitriptyline, reversed depressive-like behaviour, whereas paroxetine unexpectedly reduced risk-taking behaviour in diabetic mice. We conclude that vortioxetine may offer therapeutic value for alleviating pain in diabetic neuropathy, particularly in patients with comorbid depression.

Background: Pain seriously impacts patients' life quality. The use of morphine for pain is common, but tolerance limits its application in clinic. However, there is no exact mechanism for tolerance. In this study, we explored how microglial polarization and IL (interleukin)-4,along with a CB2 receptor agonist, affect reducing morphine tolerance.

Method: The cells cultivated with morphine or combined CB2R agonist AM1241, CB2R antagonist AM630, CB1R antagonist AM281, and IL-4 inhibitor (IL-4I).Mice were injected with these drugs for 7 days, and hot plate behavioral tests were performed 30 min after administration respectively. Mice received a single morphine injection on day 8.Samples were taken post-tests. The expression of iNOS, SOCS3, IL-4 and STAT6 mRNA were detected by qPCR; the expression of iNOS, SOCS3, p-STAT6 and STAT6 protein were detected by Western blot. Inflammatory cytokines were detected with Elisa kit.

Results: The M1 marker iNOS increased, the M2 marker SOCS3 decreased, p-STAT6 protein did not change, and the cytokines increased after morphine treatment. The paw withdrawal latency (PWL) value, IL-4 mRNA and p-STAT6 protein increased after AM1241 treatment, iNOS decreased and SOCS3 increased after AM1241 treatment, AM1241 decreased the pro-inflammatory cytokines, increased IL-4, IL-10 secretion. AM630 and IL-4I reversed the effect of AM1241 on PWL, M1 M2 markers.

Conclusion: The polarization of microglia in the direction of M1 caused morphine tolerance, AM1241 increased the IL-4 mRNA and induced the phosphorylation protein of STAT6 to reduce the tolerance, and AM1241 induced microglia to polarization in the direction of M2. AM1241 regulated microglia polarization through IL-4/STAT6 pathway, thereby reducing tolerance.

Diabetic peripheral neuropathy (DPN) is the most common complication of diabetes. Half of DPN patients experience sensory deficits including loss of sensation and pain. Loss of sensation increases the risk of unnoticed foot injuries which combined with poor circulation and healing lead to amputation. Type 2 diabetes accounts for 50% of foot amputation highlighting the significant impact sensory loss can have on patients' quality of life. However, the cellular basis underlying sensory loss in DPN remains unclear. We characterized diabetes-induced neuronal loss and damage in dorsal root ganglia (DRG) in the db/db mouse model of type 2 diabetes. Morphometric characterization was carried out on two neuronal populations in lumbar DRGs of 32-week diabetic (db/db) mice. These are the N200-positive neurons, a marker for low and high-threshold mechanosensitive sensory and proprioceptive neurons, and peripherin (PRPH)-positive neurons, a marker for pain sensing neurons. In diabetic mice, N200-positive neurons were reduced by 30%. Furthermore, diabetes increased the percentage of N200-positive neurons with cytoplasmic vacuoles, a sign of damage and stress, by 2.44 fold. In addition, the average number of vacuoles was 1.6 fold higher in diabetic mice. Therapies aimed at reducing this loss could help patients better protect their limbs from injuries and thus reduce amputations.

Depression is commonly observed in individuals suffering from chronic pain, but the exact molecular mechanisms behind these symptoms are still not fully understood. This study highlights the important role of the TRIM14-NF-κB pathway in the anterior cingulate cortex (ACC) in regulating comorbid depressive symptoms associated with chronic pain. Our results show that the CFA model induces both chronic pain and depression-like behaviors in mice, with significant activation of the ACC brain regions. Specifically, the protein expression of TRIM14 was notably elevated in the ACC of CFA mice. Furthermore, reducing TRIM14 expression alleviated both chronic pain and depression-like behaviors in these mice. In addition, we also discovered that NF-κB may act as a downstream target of TRIM14, as silencing TRIM14 expression led to a reduction in the levels of phosphorylated NF-κB. Notably, inhibiting NF-κB produced similar improvements in chronic pain and depression-like behaviors, mirroring the effects observed with TRIM14 knockdown. In summary, our findings emphasize the critical role of the TRIM14-NF-κB pathway in regulating chronic pain and depression-like behaviors in the CFA mouse model. These insights provide a foundation for further exploration of the molecular mechanisms underlying chronic pain and depression, and may guide the development of targeted therapeutic strategies.

The opioid crisis has highlighted the urgent need for alternative pain management strategies. This review explores novel non-opioid targets and pathways involved in pain modulation, highlighting advancements in understanding and therapeutic potential. Pain, a multifaceted phenomenon with nociceptive, neuropathic, and inflammatory components, involves intricate molecular signaling cascades. Key pathways reviewed include voltage-gated sodium channels (Nav1.7, Nav1.8, Nav1.9), inflammasome complexes (NLRP3), the kynurenine pathway, prostaglandins, and bradykinin-mediated signaling. Emerging therapeutics such as selective Nav channel blockers, NLRP3 inhibitors, kynurenine pathway modulators, EP receptor antagonists, and bradykinin receptor antagonists offer promising alternatives to opioids. Despite challenges in clinical translation, these developments signal a paradigm shift in pain management, with precision-focused therapies poised to address unmet needs. This review emphasizes the importance of integrating molecular insights into the development of safer, more effective analgesics, setting the stage for transformative advancements in non-opioid pain relief.

Lumbar disc herniation (LDH) refers to a pathological state in which the nucleus pulposus (NP) protrudes, leading to compression or irritation of nerve roots. This condition manifests with clinical symptoms including lower back and leg pain, hyperalgesia, and altered sensory perceptions. Depending upon clinical observations, the administration of centrally acting analgesic has been associated with the alleviation of pain symptoms LDH patients. The central nervous system sensitization performs a crucial role in pain-regulating perception in LDH. Nevertheless, the precise neural circuitry and mechanism of action remain enigmatic. In the present study, we observed the activation of glutamatergic neurons in the Paraventricular nucleus of the hypothalamus (PVN) and Prelimbic cortex (PrL) in LDH rats. Experimental validation using viral tracers confirmed the existence of a projection pathway between the PVN and PrL. Inhibition of the input from PVN glutamatergic neurons to PrL glutamatergic neurons alleviates chronic pain in LDH, whereas activation of the PVN^Glu-PrL^Glu projection induces chronic pain in rats. These findings imply a pivotal role for the PVN^Glu-PrL^Glu circuit in the regulation of chronic pain in LDH.

Patients with preoperative pathological conditions such as anxiety, depression, and sleep disorders experience more severe postoperative pain, suggesting that preoperative pathological changes in patients may affect postoperative pain. However, the potential pathophysiological changes associated with postoperative pain remain unknown. Here, this study initially employed clinical research to investigate potential pathophysiological changes related to postoperative pain. Subsequently, animal behavioral experiments and mechanistic explorations were conducted accordingly. Pregnant women undergoing cesarean sections who could provide preoperative cerebrospinal fluid were selected as subjects. Preoperative cerebrospinal fluid proteomics, postoperative pain intensity, and neutrophil-to-lymphocyte ratio (NLR) were analyzed. Rats were used to model the corresponding preoperative pathological state. Mechanical pain thresholds were measured after plantar incision and spinal cords were harvested for analysis. Clinical studies showed that one-quarter of the proteins positively correlated with postoperative pain were related to reactive oxygen species (ROS). Furthermore, the NLR-Ratio, reflecting postoperative inflammation level, increased with the severity of postoperative pain. Establishing a preoperative ROS-increased model with oxidant t-BOOH enhanced postoperative acute mechanical hyperalgesia and spinal neuroinflammation in rats. Conversely, preoperative administration of antioxidant VE, reducing ROS, alleviated postoperative hyperalgesia and spinal neuroinflammation. galectin-3 inhibitors mitigated postoperative hyperalgesia and neuroinflammation in the preoperative ROS-increased model. Additionally, The effects of galectin-3 on pain sensitization and pro-inflammation in vitro were mediated by the TLR4 receptor. Thus, this study demonstrated that preoperative ROS exacerbated postoperative hyperalgesia via galectin-3-mediated neuroinflammation, suggesting that galectin-3 may be a potential therapeutic target for alleviating postoperative pain in clinical patients.

Anterolateral system (ALS) projection neurons underlie perception of pain, itch and skin temperature. These cells are heterogeneous, and there have therefore been many attempts to define functional populations. A recent study identified two classes of ALS neuron in mouse superficial dorsal horn (SDH) based on expression of the G protein-coupled receptors Tacr1 or Gpr83. It was reported that cells expressing these receptors formed largely non-overlapping populations, and that ~60% of ALS cells in SDH expressed Tacr1. An additional finding was that while Tacr1- and Gpr83-expressing ALS cells projected to several brain nuclei, their axons did not reach the ventral posterolateral (VPL) thalamic nucleus, which is reciprocally connected to the primary somatosensory cortex. These results were surprising, because we had reported that ~90% of SDH ALS neurons in the mouse possess the neurokinin 1 receptor (NK1r), which is encoded by Tacr1, and in addition the VPL is thought to receive input from lamina I ALS cells. Here we use retrograde and anterograde labelling in Tacr1^CreERT2 and Gpr83^CreERT2 mice to reinvestigate the expression of the receptors by ALS neurons and to reassess their projection patterns. We find that ~90% of ALS neurons in SDH express Tacr1, with 40%-50% expressing Gpr83. We also show that axons of both Tacr1- and Gpr83-expressing ALS neurons reach the VPL. These results suggest that ALS neurons in the SDH that express these GPCRs show considerable overlap, and that they are likely to contribute to the sensory-discriminative dimension of pain through their projections to VPL.