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The spinal phosphodiesterase-4 (PDE4) plays an important role in chronic pain. Inhibition of PDE4, an enzyme catalyzing the hydrolysis of cyclic adenosine monophosphate AMP (cAMP), produces potent antinociceptive activity. However, the antinociceptive mechanism remains largely unknown. Connexin43 (Cx43), a gap junction protein, has been shown to be involved in controlling pain transduction at the spinal level; restoration of Cx43 expression in spinal astrocytes to the normal levels reduces nerve injury-induced pain. Here, we evaluate the novel mechanisms involving spinal cAMP-Cx43 signaling by which PDE4 inhibitors produce antinociceptive activity.
Learn More >Interdisciplinary pain rehabilitation programs (IPRPs) are evidence-based treatments for chronic pain. Previous research has demonstrated that initial presentations of adult men and women admitted to IPRPs differ, but less is known about sex differences in IPRP treatment outcomes. To summarize and synthesize the current literature base on this topic, a systematic literature review was conducted that asked: are sex differences present in participant outcomes upon completion of interdisciplinary pain rehabilitation programs for cisgender patients? Four core domains of outcome measures were assessed: depression, pain catastrophizing, pain interference, and pain intensity/severity.
Learn More >Music intervention (MI) has been applied as an effective adjunctive treatment for pain control in various clinical settings. However, no meta-analysis has yet been published on the analgesic effects of MI in infants and children. We performed a systematic review of PubMed, EMBASE, Web of Science, and Cochrane Library databases to identify randomized controlled trials (RCTs) with the keywords "pain" AND "music therapy" from inception to January 2022. Primary outcomes were pain intensity and vital signs. Standardized mean difference (SMD) values and the corresponding 95% confidence intervals (CIs) were computed using a random effect model. Subgroup analyses with age groups, types of pain, and music styles were conducted. A total of 38 RCTs involving 5601 participants met the selection criteria. MI significantly decreased the pain levels (SMD = -0.57, < 0.001), both in the newborn group ( = 0.007) and in the infant/children group ( < 0.001). MI significantly reduced heart rate (SMD = -0.50, < 0.001) and respiratory rate (SMD = -0.60, = 0.002) and increased peripheral capillary oxygen saturation (SMD = 0.44, < 0.001). In subgroup analyses of types of pain, MI had significant effects on prick pain ( = 0.003), chronic and procedural pain ( < 0.001), and postoperative pain ( = 0.018). As for music styles, significant analgesic effects were observed for classical music ( < 0.001), kids' music ( < 0.001), and pop music ( = 0.001), but not for world music ( = 0.196), special composition ( = 0.092), and multiple music combinations ( = 0.420). In conclusion, our analysis provides supportive evidence about the efficacy of MI, especially classical, kids', and pop music, in controlling prick, procedural, and postoperative pain in the pediatric population.
Learn More >Toll-like receptors (TLRs) are innate immune receptors that are expressed in immune cells as well as glia and neurons of the central and peripheral nervous systems. They are best known for their role in the host defense in response to pathogens and for the induction of inflammation in infectious and non-infectious diseases. In the central nervous system (CNS), TLRs modulate glial and neuronal functions as well as innate immunity and neuroinflammation under physiological or pathophysiological conditions. The majority of the studies on TLRs in CNS pathologies investigated their overall contribution without focusing on a particular cell type, or they analyzed TLRs in glia and infiltrating immune cells in the context of neuroinflammation and cellular activation. The role of neuronal TLRs in CNS diseases and injuries has received little attention and remains underappreciated. The primary goal of this review is to summarize findings demonstrating the pivotal and unique roles of neuronal TLRs in neuropathic pain, Alzheimer's disease, Parkinson's disease and CNS injuries. We discuss how the current findings warrant future investigations to better define the specific contributions of neuronal TLRs to these pathologies. We underline the paucity of information regarding the role of neuronal TLRs in other neurodegenerative, demyelinating, and psychiatric diseases. We draw attention to the importance of broadening research on neuronal TLRs in view of emerging evidence demonstrating their distinctive functional properties.
Learn More >Galcanezumab, a monoclonal antibody against calcitonin gene-related peptide, is an emerging migraine preventative. We hypothesized that the preventive effects are conveyed via modulation of somatosensory processing and that certain sensory profiles may hence be associated with different clinical responses. We recruited migraine patients (n=26), who underwent quantitative sensory tests (QST) over the right V1 dermatome and forearm at baseline (T0), 2-3 weeks (T1), and one year (T12) after monthly galcanezumab treatment. The clinical response was defined as a reduction of ≥30% in headache frequency based on the headache diary. Predictors for clinical response were calculated using binary logistical regression models. After galcanezumab (T1 vs. T0), the heat pain threshold (HPT) (°C, 44.9 ± 3.4 vs. 43.0 ± 3.3, p=0.013) and mechanical pain threshold (MPT) (log mN, 1.60 ± 0.31 vs. 1.45 ± 0.26, p=0.042) were increased exclusively in the V1 dermatome, but not the forearm. These changes were immediate, did not differ between responders and non-responders, and did not last in one year of follow-up (T12 vs. T0). However, baseline HPT (OR: 2.13, 95% CI: 1.08-4.19, p = 0.029) on the forearm was a robust predictor for a clinical response three months later. In summary, our data demonstrated that galcanezumab modulates pain thresholds specifically in the V1 dermatome, but this modulation is short-lasting and irrelevant to clinical response. Instead, the clinical response may be determined by individual sensibility even before the administration of medication.
Learn More >Dorsal root ganglion (DRG) neurons are classified into distinct types to mediate the somatosensation with different modalities. Recently, transcriptional profilings of DRG neurons by single-cell RNA-sequencing have provided new insights into the neuron typing and functional properties. Zinc-finger CCHC domain-containing 12 (Zcchc12) was reported to be the representative marker for a subtype of Gal-positive (Gal) DRG neurons. However, the characteristics and functions of Zcchc12 neurons are largely unknown. Here, we genetically labelled Zcchc12 neurons in Zcchc12-CreERT2::Ai9 mice, and verified that Zcchc12 represented a new subpopulation of DRG neurons in both sexes. Zcchc12 neurons centrally innervated the superficial laminae in spinal dorsal horn, and peripherally terminated as free nerve endings in the epidermis and cluster-shaped fibers in the dermis of footpads and nearby. Besides, Zcchc12 neurons also formed circumferential endings surround the hair follicles in hairy skin. Functionally, calcium imaging in DRGs revealed that Zcchc12 neurons were polymodal nociceptors and could be activated by mechanical and noxious thermal stimuli. Behavioral tests showed that selective ablation of Zcchc12 DRG neurons reduced the sensitivity to noxious heat in mice. Taken together, we identify a new subpopulation of Zcchc12 nociceptors essential for noxious heat sensation.Zcchc12 represents a new subpopulation of DRG neurons. The characteristics and functions of Zcchc12 neurons are largely unknown. Here we genetically labelled Zcchc12 neurons, and showed that the fibers of Zcchc12 DRG neurons projected to superficial lamina at spinal dorsal horn, and innervated skin as free nerve endings in the epidermis and cluster-shaped fibers in the dermis of footpads and nearby. Functionally, Zcchc12 DRG neurons responded to noxious mechanical and heat stimuli. Ablation of Zcchc12 DRG neurons impaired the sensation of noxious heat in mice. Therefore, we identify a new subpopulatipn of DRG neurons required for noxious heat sensation.
Learn More >There is limited evidence regarding the possible role of dietary acid load (DAL) in the pathophysiology of migraine headaches. Therefore, we sought to examine DAL in relation to the clinical features of migraine including headache frequency, severity and duration, headache impact test-6 (HIT-6), and serum levels of nitric oxide (NO). In the present cross-sectional study, 262 patients (38 men and 224 women aged 20-50 years) were recruited through a simple random sampling method. Dietary intakes were obtained by using a validated 168-item semi-quantitative food frequency questionnaire (FFQ). DAL was then calculated by two different methods; potential renal acid load (PRAL) and net endogenous acid production (NEAP). In total, 262 patients with a mean (SE) age of 36.1 (0.53) and a BMI of 25.55 (0.21) were included in the current study. After controlling for potential confounders, a higher DAL was positively associated with headache frequency in those with the highest DAL score compared to the lowest (PRAL; β = 2.33; 95% CI 0.78, 3.88; NEAP; β = 1.74; 95% CI 0.13, 3.34). Increasing NEAP from 28.96 to 35.89 resulted in a 3.43 and 2.74 increment in HIT-6 scores in the crude (95% CI 1.35, 5.52) and fully-adjusted models (95% CI 0.40, 5.07), respectively. Moreover, a higher dietary PRAL was significantly associated with migraine-related disability, as shown by HIT-6, in subjects of the third tertile compared to those in the first tertile after controlling for confounders (β = 2.42; 95% CI 0.13, 4.70). In conclusion, our study highlighted the importance of the acid-base properties of a diet in the pathophysiology of migraine headaches. However, further well-designed studies are needed to confirm our findings.
Learn More >While the general relationship between ACEs and the development of chronic pain has become increasingly clear, how ACEs may shape a child's clinical presentation with regards to chronic pain has yet to be fully expounded. We aimed to determine the association between ACEs and clinical manifestations of pediatric chronic pain and explore the interaction of ACEs and pediatric rheumatic disease among youth with chronic pain on health-related outcomes.
Learn More >Osteoarthritis (OA) is a chronic condition. Physiotherapy is known to be beneficial for people with OA. Patient adherence to physiotherapy exercise is essential for the effective management of OA.
Learn More >Somatosensory neurons in dorsal root ganglia (DRG) comprise several main subclasses: high threshold nociceptors/thermoceptors, high- and low-threshold mechanoreceptors, and proprioceptors. Recent years have seen an explosion in the identification of molecules that underlie the functional diversity of these sensory modalities. They also have begun to reveal the developmental mechanisms that channel the emergence of this subtype diversity, solidifying the importance of peripheral instructive signals. Somatic sensory neurons collectively serve numerous essential physiological and protective roles, and as such, an increased understanding of the processes that underlie the specialization of these sensory subtypes is not only biologically interesting but also clinically relevant.
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