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Comorbid chronic pain and depression are increasingly becoming a concerning public problem, but the underlying mechanisms remain unclear. Here, we demonstrate that pain-related depression-like behaviors are induced in a rat model of chronic constriction injury (CCI). Using this model, we found that chronic neuropathic pain decreased the activity and expression of sirtuin 1 (SIRT1, an NAD-dependent deacetylase) in the central nucleus of the amygdala (CeA). In addition, the pharmacologic activation of SIRT1 in the CeA could alleviate the depression-like behaviors associated with chronic pain while relieving sensory pain. Accordingly, adeno-associated virus (AAV)-mediated SIRT1 overexpression in the CeA produced a positive effect on the easement of chronic pain and comorbid depression. Taken together, these findings highlight the role of SIRT1 in the CeA in chronic pain and depression states and reveal that the upregulation of SIRT1 may be a potential therapy for the treatment of pain-depression comorbidities.
Learn More >The neuronal-type (N-type) voltage-gated calcium (Ca) channels, which are designated Ca2.2, have an important role in the release of neurotransmitters. Ziconotide is a Ca2.2-specific peptide pore blocker that has been clinically used for treating intractable pain. Here we present cryo-electron microscopy structures of human Ca2.2 (comprising the core α1 and the ancillary α2δ-1 and β3 subunits) in the presence or absence of ziconotide. Ziconotide is thoroughly coordinated by helices P1 and P2, which support the selectivity filter, and the extracellular loops (ECLs) in repeats II, III and IV of α1. To accommodate ziconotide, the ECL of repeat III and α2δ-1 have to tilt upward concertedly. Three of the voltage-sensing domains (VSDs) are in a depolarized state, whereas the VSD of repeat II exhibits a down conformation that is stabilized by Ca2-unique intracellular segments and a phosphatidylinositol 4,5-bisphosphate molecule. Our studies reveal the molecular basis for Ca2.2-specific pore blocking by ziconotide and establish the framework for investigating electromechanical coupling in Ca channels.
Learn More >Chemotherapy-induced peripheral neuropathy ((CI)PN) becomes chronic in 30% of cancer patients. Knowledge of predictors of chronic (CI)PN and related impairments in health-related quality of life (HRQoL) is lacking. We examined the role of optimism in chronic (CI)PN severity and associated HRQoL in colorectal cancer (CRC) patients up to two years after diagnosis.
Learn More >Slow, deep breathing (SDB) is a common pain self-management technique. Stimulation of the arterial baroreceptors and vagal modulation are suggested, among others, as potential mechanisms underlying the hypoalgesic effects of SDB. We tested whether adding an inspiratory load to SDB, which results in a stronger baroreceptor stimulation and vagal modulation, enhances its hypoalgesic effects. Healthy volunteers performed SDB (controlled at 0.1 Hz) with and without an inspiratory threshold load. Controlled breathing (CB) at a normal frequency (0.23 Hz) was used as an active control. Each condition lasted 90 s, included an electrical pain stimulation on the hand, and was repeated four times in a randomized order. Pain intensity, self-reported emotional responses (arousal, valence, dominance), and cardiovascular parameters (including vagally-mediated heart rate variability) were measured per trial. A cover story was used to limit the potential effect of outcome expectancy. Pain intensity was slightly lower during SDB with load compared with normal-frequency CB, but the effect was negligible (Cohens d < 0.2), and there was no other difference in pain intensity between the conditions. Heart rate variability was higher during SDB with/without load compared with normal-frequency CB. Using load during SDB was associated with higher heart rate variability, but less favorable emotional responses. These findings do not support the role of baroreceptor stimulation or vagal modulation in the hypoalgesic effects of SDB. Other mechanisms, such as attentional modulation, warrant further investigation.
Learn More >The neurophysiological mechanisms underlying NGF-induced masseter muscle sensitization and sex-related differences in its effect are not well understood in humans. Therefore, this longitudinal cohort study aimed to investigate the effect of NGF injection on the density and expression of substance P, NMDA-receptors and NGF by the nerve fibers in the human masseter muscle, to correlate expression with pain characteristics, and to determine any possible sex-related differences in these effects of NGF. The magnitude of NGF-induced mechanical sensitization and pain during oral function was significantly greater in women than in men (P < 0.050). Significant positive correlations were found between nerve fiber expression of NMDA-receptors and peak pain intensity (r = 0.620, P = 0.048), and expression of NMDA-receptors by putative nociceptors and change in temporal summation pain after glutamate injection (r = 0.561, P = 0.003). In women, there was a significant inverse relationship between the degree of NGF-induced mechanical sensitization and the change in nerve fiber expression of NMDA-receptors alone (r = - 0.659, P = 0.013), and in combination with NGF (r = - 0.764, P = 0.001). In conclusion, women displayed a greater magnitude of NGF-induced mechanical sensitization that also was associated with nerve fibers expression of NMDA-receptors, when compared to men. The present findings suggest that, in women, increased peripheral NMDA-receptor expression could be associated with masseter muscle pain sensitivity.
Learn More >Migraine affects roughly 10% of youth aged 5-15 years, however the underlying mechanisms of migraine in youth are poorly understood. Multiple structural and functional alterations have been shown in the brains of adult migraine sufferers. This study aims to investigate the effects of migraine on resting-state functional connectivity during the period of transition from childhood to adolescence, a critical period of brain development and the time when rates of pediatric chronic pain spikes.
Learn More >Frequent nightly arousals typical for sleep disorders cause daytime fatigue and present health risks. As such arousals are often short, partial, or occur locally within the brain, reliable characterization in rodent models of sleep disorders and in human patients is challenging. We found that the EEG spectral composition of non-rapid-eye-movement sleep (NREMS) in healthy mice shows an infraslow (~50 s) interval over which microarousals appear preferentially. NREMS could hence be vulnerable to abnormal arousals on this time scale. Chronic pain is well-known to disrupt sleep. In the spared-nerve-injury (SNI) mouse model of chronic neuropathic pain, we found more numerous local cortical arousals accompanied by heart rate increases in hindlimb primary somatosensory, but not in prelimbic, cortices, although sleep macroarchitecture appeared unaltered. Closed-loop mechanovibrational stimulation further revealed higher sensory arousability. Chronic pain thus preserved conventional sleep measures but resulted in elevated spontaneous and evoked arousability. We develop a novel moment-to-moment probing of NREMS vulnerability and propose that chronic pain-induced sleep complaints arise from perturbed arousability.
Learn More >Association of temporomandibular disorders (TMD)-related pain with severe headaches (migraine and tension-type headaches [TTH]) was studied over a follow-up period of 11 years.
Learn More >Preclinical studies demonstrate that cannabidiol (CBD) elicits an antinociceptive response in animal models of neuropathic pain; in humans, limited data are available to support such analgesic effects. Few studies have examined CBD's analgesic effects when administered without other compounds, and little is known regarding dose-dependent effects in non-cannabis users.
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