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No externally validated presurgical risk score for chronic postsurgical pain (CPSP) is currently available. We tested the generalizability of a six-factor risk model for CPSP developed from a prospective cohort of 2929 patients in four surgical settings. Seventeen centers enrolled 1225 patients scheduled for inguinal hernia repair, hysterectomy (vaginal or abdominal), or thoracotomy. The six clinical predictors were surgical procedure, younger age, physical health (Short Form Health Survey-12), mental health (Short Form Health Survey-12), preoperative pain in the surgical field, and preoperative pain in another area. CPSP was confirmed by physical examination at 4 months. The model's discrimination (c-statistic), calibration, and diagnostic accuracy (sensitivity, specificity and positive and negative likelihood ratios) were calculated to assess geographic and temporal transportability in the full cohort and two subsamples (historical and new centers). The full dataset after exclusions and losses included 1088 patients; 20.6% had developed CPSP at 4 months. The c-statistics (95% CI) were similar in the full validation sample and the two subsamples: 0.69 (0.65-0.73), 0.69 (0.63-0.74) and 0.68 (0.63-0.74), respectively. Calibration was good (slope b and intercept close to 1 and 0, respectively and nonsignificance in the Hosmer-Lemeshow goodness-of-fit test). The validated model based on six clinical factors reliably identifies risk for CPSP risk in about 70% of patients undergoing the surgeries studied, allowing surgeons and anesthesiologists to plan and initiate risk reduction strategies in routine practice and researchers to screen for risk when randomizing patients in trials.
Learn More >Primary burning mouth syndrome (BMS) is an orofacial disease with neuropathic characteristics. Psychophysics, such as quantitative sensory testing (QST) are used to sub-classify neuropathic pain syndromes, but their usefulness in characterizing BMS is not yet clear.
Learn More >As treatment for postsurgical pain (PSP) remains a major unmet medical need, the emergence of safe and innovative non-opioid drugs has been strongly coveted. Tetrahydrobiopterin (BH4) is an interesting molecule for gaining a better understanding the pathological mechanism of neuropathic pain. However, whether BH4 and its pathway are involved in the pathogenesis of PSP remains unclear. In this study, we found that early in a rat paw incision model, the gene expression of GTP cyclohydrolase 1 (GTPCH) and sepiapterin reductase (SPR), BH4-producing enzymes in the de novo pathway, were significantly increased in incised compared with naïve paw skin. Although a significant increase in GTPCH protein levels was observed in incised paw skin until only 1 day after incision, a significant increase in BH4 levels was observed until 7 days after incision. In vivo, Spr-knockout mice showed an antinociceptive phenotype in the hind paw incision compared with the wild-type and Spr heterozygote groups. Furthermore, QM385, the SPR inhibitor, showed a significant dose-dependent, antinociceptive effect, which was supported by a reduction in BH4 levels in incised skin tissues, with no apparent adverse effects. Immunohistochemical analysis demonstrated that macrophages expressing GTPCH protein were increased around the injury site in the rat paw incision model. These results indicate that BH4 is involved in the pathogenesis of PSP, and that inhibition of the BH4 pathway could provide a new strategy for the treatment of acute PSP.
Learn More >Migraine is commonly reported among patients with temporomandibular disorders (TMDs), especially myogenic TMD. The pathophysiologic mechanisms related to the comorbidity of the two conditions remain elusive. In the present study, we combined masseter muscle tendon ligation (MMTL)-produced myogenic TMD with systemic injection of nitroglycerin (NTG)-induced migraine-like hypersensitivity in mice. Facial mechanical allodynia, functional allodynia, and light-aversive behavior were evaluated. Sumatriptan, an FDA-approved medication for migraine, was used to validate migraine-like hypersensitivity. Additionally, we examined the protein level of calcitonin gene-related peptide (CGRP) in the spinal trigeminal nucleus caudalis using immunohistochemistry. We observed that mice with MMTL pretreatment have a prolonged NTG-induced migraine-like hypersensitivity, and MMTL also enabled a non-sensitizing dose of NTG to trigger migraine-like hypersensitivity. Systemic injection of sumatriptan inhibited the MMTL-enhanced migraine-like hypersensitivity. MMTL pretreatment significantly upregulated the protein level of CGRP in the spinal trigeminal nucleus caudalis after NTG injection. Our results indicate that a pre-existing myogenic TMD can upregulate NTG-induced trigeminal CGRP and enhance migraine-like hypersensitivity.
Learn More >Placebos can reduce pain by inducing beliefs in the effectiveness of an actually inert treatment. Such top-down effects on pain typically engage lateral and medial prefrontal regions, the insula, somatosensory cortex, as well as the thalamus and brainstem during pain anticipation or perception. Considering the level of large-scale brain networks, these regions spatially align with fronto-parietal/executive control, salience, and sensory-motor networks, but it is unclear if and how placebos alter interactions between them during rest. Here, we investigated how placebo analgesia affected intrinsic network coupling. Ninety-nine human participants were randomly assigned to a placebo or control group and underwent resting-state fMRI after pain processing. Results revealed inverse coupling between two resting-state networks in placebo but not control participants. Specifically, networks comprised the bilateral somatosensory cortex and posterior insula, as well as the brainstem, thalamus, striatal regions, dorsal and rostral anterior cingulate cortex, and the anterior insula, respectively. Across participants, more negative between-network coupling was associated with lower individual pain intensity as assessed during a preceding pain task, and there was no significant relation with expectations of medication effectiveness in the placebo group. Altogether, these findings provide initial evidence that placebo analgesia affects the intrinsic communication between large-scale brain networks, even in the absence of pain. We suggest a theoretical model where placebo analgesia might affect processing within a descending pain-modulatory network, potentially segregating it from somatosensory regions that may code for painful experiences.
Learn More >Chronic neuropathic pain is a highly disabling syndrome that is poorly controlled by currently available analgesics. Here, we show that painful symptoms and associated cognitive deficits induced by spinal nerve ligation in the rat are prevented by the administration of serotonin 5-HT receptor inverse agonists or by the mTOR inhibitor rapamycin. In contrast, they are not alleviated by the administration of 5-HT receptor neutral antagonists. Likewise, activation of mTOR by constitutively active 5-HT receptors mediates allodynia in oxaliplatin-induced peripheral neuropathy in rats but not mechanical nociception in healthy rats. Furthermore, both painful and co-morbid cognitive symptoms in neuropathic rats are strongly reduced by intrathecal delivery of a cell-penetrating peptide that disrupts 5-HT receptor/mTOR physical interaction. Collectively, these findings demonstrate a deleterious influence of non-physiological mTOR activation by constitutively active spinal 5-HT receptors upon painful and cognitive symptoms in neuropathic pains of different etiologies. They suggest that targeting the constitutive activity of 5-HT receptors with inverse agonists or disrupting the 5-HT receptor/mTOR interaction might be valuable strategies for the alleviation of neuropathic pain and cognitive co-morbidities.
Learn More >Management of chronic pain presents a major challenge, since many currently available treatments lack efficacy and have problems such as addiction and tolerance. Loss of function mutations in the SCN9A gene lead to a congenital inability to feel pain, with no other sensory deficits aside from anosmia. SCN9A encodes the voltage-gated sodium (Na) channel 1.7 (Na1.7), which has been identified as a primary pain target. However, in developing Na1.7-targeted analgesics, extreme care must to be taken to avoid off-target activity on other Na subtypes that are critical for survival. Since spider venoms are an excellent source of Na channel modulators, we screened a panel of spider venoms to identify selective Na1.7 inhibitors. This led to identification of two novel Na modulating venom peptides (β/μ-theraphotoxin-Pe1a and β/μ-theraphotoxin-Pe1b (Pe1b) from the arboreal tarantula Phormingochilus everetti. A third peptide isolated from the tarantula Bumba pulcherrimaklaasi was identical to the well-known ProTx-I (β/ω-theraphotoxin-Tp1a) from the tarantula Thrixopelma pruriens. A tethered toxin (t-toxin)-based alanine scanning strategy was used to determine the Na1.7 pharmacophore of ProTx-I. We designed several ProTx-I and Pe1b analogues, and tested them for activity and Na channel subtype selectivity. Several analogues had improved potency against Na1.7, and altered specificity against other Na channels. These analogues provide a foundation for development of Pe1b as a lead molecule for therapeutic inhibition of Na1.7.
Learn More >Recent studies have shown that the endogenous opioid system is considerably affected by early life stress such as child abuse. Here, we investigated whether early life stress changes the endogenous opioid receptors and their peptides, and if such stress impacts morphine antinociception. We used mice affected by maternal separation and social isolation (MSSI) as an early life stress model. In the tail-flick test, 10-week-old MSSI mice showed a significant decrease in morphine antinociception compared to age-matched control mice. The number of c-Fos-positive cells increased in the periaqueductal gray (PAG), nucleus accumbens, and thalamus of control mice after the morphine injections, whereas hardly any positive cells were detected in the same areas of MSSI mice. The expression of μ- and κ-opioid receptor (MOR and KOR, respectively) messenger RNA (mRNA) was significantly decreased in the PAG of MSSI mice, whereas KOR expression was significantly increased in the amygdala of MSSI mice. The expression of δ-opioid receptor (DOR) mRNA was significantly reduced in the PAG and rostral ventromedial medulla of MSSI mice compared to control mice. Moreover, the lack of morphine antinociception was observed in 18-week-old MSSI mice. Our findings suggest that the supraspinal opioid system may be affected by early life stress exposure, and that this exposure may impact morphine antinociception.
Learn More >Mechano growth factor (MGF) is an alternatively spliced form of insulin-like growth factor-1 (IGF-1) that has shown to be neuroprotective against 6-hydroxydopamine toxicity and ischemic injury in the brain. MGF also induces neural stem cell proliferation in the hippocampus and preserves olfactory function in aging mice. Cisplatin is a chemotherapy drug that induces peripheral neuropathy in 30-40% of treated patients. Our studies were designed to see if MGF would protect dorsal root ganglion (DRG) neurons from cisplatin-induced neurotoxicity and to identify potential mechanisms that may be involved. Expression of endogenous MGF in adult DRG neurons in vivo ameliorated cisplatin-induced thermal hyperalgesia. Exogenous MGF and MGF with a cysteine added to the N-terminus (CMGF) also protected embryonic DRG neurons from cisplatin-induced cell death in vitro. Mass spectroscopy analysis of proteins bound to MGF showed that nucleolin is a key-binding partner. Antibodies against nucleolin prevented the neuroprotective effect of MGF and CMGF in culture. Both nucleolin and MGF are located in the nucleolus of DRG neurons. RNAseq of RNA associated with MGF indicated that MGF may be involved in RNA processing, protein targeting and transcription/translation. Nucleolin is an RNA binding protein that is readily shuttled between the nucleus, cytoplasm and plasma membrane. Nucleolin and MGF may work together to prevent cisplatin-induced neurotoxicity. Exploring the known mechanisms of nucleolin may help us better understand the mechanisms of cisplatin toxicity and how MGF protects DRG neurons.
Learn More >Pain from burn injuries is among the most excruciating encountered in clinical practice. Pharmacological methods often fail to achieve acceptable level of analgesia in these patients, especially during burn wound dressing and debridement. Virtual reality (VR) distraction is a promising analgesic technique that progressed significantly in the last decade with development of commercially available, low-cost, high-resolution, wide field-of-view, standalone VR devices that can be used in many clinical scenarios. VR has demonstrated clinical benefit as an adjunctive analgesic during burn wound dressing and other painful medical procedures. The technique has proven useful also in preparing patients for magnetic resonance imaging scans, particularly in claustrophobic patients. Modulation of pain-related brain activity at cortical and subcortical levels by VR, and its correlation with subjective improvement in various laboratory and clinical pain experiences has been demonstrated using multiple functional brain imaging studies including functional magnetic resonance imaging and brain perfusion single photon emission computed tomography.
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