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Chronic morphine exposure persistently activates Gαi/o protein-coupled receptors and enhances adenylyl cyclase (AC) activity, which can increase cyclic adenosine monophosphate (cAMP) production. Direct binding of cAMP to the cytoplasmic site on hyperpolarization-activated cyclic nucleotide-gated (HCN) channels increases the probability of channel opening. HCN channels play a prominent role in chronic pain the disease that shares some common mechanisms with opioid tolerance. This compensatory AC activation may be responsible for the induction of morphine-induced analgesic tolerance. We investigated spinal cAMP formation and expression of HCN2 in the spinal cord, and observed the effect of AC inhibition on the induction of morphine analgesic tolerance. We found that chronic morphine-induced antinociceptive tolerance increased spinal cAMP formation and the expression of spinal HCN2. Inhibition of spinal AC partially blocked chronic morphine-induced cAMP formation and prevented the induction of morphine-induced analgesic tolerance. Inhibition of HCN2 also showed a partial preventive effect on morphine-induced tolerance, hypothermia tolerance and also the right-shift of the dose-response curve. We conclude that repeated morphine treatment increases AC activity and cAMP formation, and also spinal HCN2 expression, blockade of AC or HCN2 can prevent the development of morphine-induced analgesic tolerance.
Learn More >Although psychological treatments benefit youth with chronic pain, treatment is not accessible in most communities. Digital health interventions offer promise for expanding access and reach to this population. Using a stepped wedge cluster randomized trial design, we evaluated effectiveness and implementation of a digital health delivered psychological intervention for pediatric chronic pain. 143 youth, ages 10-17 with chronic pain and a caregiver were recruited from 8 clinics in the United States. Active intervention included access to the WebMAP Mobile App and the WebMAP parent website to learn pain self-management skills. Effectiveness outcomes included pain intensity, disability, and patient global impression of change (PGIC), while Reach, Adoption, Implementation, and Maintenance were implementation outcomes. Results showed that youth in both treatment conditions (WebMAP vs Usual Care) had similar changes over time in pain and disability. Youth in the WebMAP condition perceived greater improvement (PGIC) at post-treatment and follow-up (d's = 0.54 and 0.44, p < .05) compared to youth receiving usual care. Use of the digital health intervention was modest and variable; about 30% of youth and parents completed treatment. Greater engagement (number of completed modules) was associated with significantly greater reductions in pain and disability from pre-treatment to follow-up (d's = -0.57 and -0.38, p < .05). Parents, youth, and providers found treatment acceptable; providers had positive attitudes and demonstrated referrals over a maintenance period. Further research is needed to understand how to enhance treatment engagement with digital health interventions and optimize implementation.
Learn More >Alterations in cellular energy metabolism have been implicated in chronic pain suggesting a role for mitochondrial DNA (mtDNA). Previous studies reported associations of a limited number of mtDNA polymorphisms with specific pain conditions. In this study, we examined the full mitochondrial genomes of people with a variety of chronic pain conditions. A discovery cohort consisting of 609 participants either with or without a complex persistent pain conditions (CPPC) was examined. mtDNA was subjected to deep sequencing for identification of rare mutations, common variants, haplogroups, and heteroplasmy associated with five CPPCs: episodic migraine, irritable bowel syndrome, fibromyalgia, vulvar vestibulitis, or temporomandibular disorders. The strongest association found was the presence of the C allele at the single nucleotide polymorphism (SNP) m.2352T>C (rs28358579) that significantly increased the risk for fibromyalgia (OR=4.6, P=4.3×10). This relationship was even stronger in women (OR=5.1, P=2.8×10), and m.2352T>C was associated with all other CPPCs in a consistent risk-increasing fashion. This finding was replicated in another cohort (OR=4.3, P=2.6×10) of the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) study consisting of 1754 female participants. To gain insight into the cellular consequences of the associated genetic variability, we conducted an assay testing metabolic reprogramming in human cell lines with defined genotypes. The minor allele C was associated with decreased mitochondrial membrane potential under conditions where oxidative phosphorylation is required, indicating a role of oxidative phosphorylation in pathophysiology of chronic pain. Our results suggest that cellular energy metabolism, modulated by m.2352T>C, contributes to fibromyalgia and possibly other chronic pain conditions.
Learn More >Glial reactivity in the dorsal horn of the spinal cord is a hallmark in most chronic pain conditions. Neuroinflammation-associated reactive glia, in particular astrocytes, have been shown to exhibit reduced mitochondrial respiratory function.Here we studied the mitochondrial function at the lumbar spinal cord tissue from Complete Freund's adjuvant (CFA)-induced inflammatory pain rat and chronic constriction injury (CCI) mouse models by high resolution respirometry (HRR). A significant decrease in mitochondrial bioenergetic parameters at the injury-related spinal cord level coincided with highest astrocytosis. Oral administration of dichloroacetate (DCA) significantly increased mitochondrial respiratory function by inhibiting pyruvate dehydrogenase kinase (PDK) and decreased GFAP and Iba-1 immunoreactivity in spinal cord. Importantly, DCA treatment significantly reduced the ipsilateral pain-related behavior without affecting contralateral sensitivity in both pain models. Our results indicate that mitochondrial metabolic modulation with DCA may offer an alternative therapeutic strategy to alleviate chronic and persistent inflammatory pain.
Learn More >Pain is evolutionarily necessary for survival in that it reduces tissue damage by signaling the body to respond to a harmful stimulus. However, in many circumstances, acute pain becomes chronic, and this is often dysfunctional. Adolescent chronic pain is a growing epidemic with an unknown etiology and limited effective treatment options. Given that the relationship between acute pain and chronic pain is not straightforward, there is a need to better understand the factors that contribute to the chronification of pain. Since early life factors are critical to a variety of outcomes in the developmental and adolescent periods, they pose promise as potential mechanisms that may underlie the transition from acute to chronic pain. This review examines two early life factors: poor diet and adverse childhood experiences (ACEs); they may increase susceptibility to the development of chronic pain following surgical procedures or traumatic brain injury (TBI). Beyond their high prevalence, surgical procedures and TBI are ideal models to prospectively understand mechanisms underlying the transition from acute to chronic pain. Common themes that emerged from the examination of poor diet and ACEs as mechanisms underlying this transition included: prolonged inflammation and microglia activation leading to sensitization of the pain system, and stress-induced alterations to hypothalamic-pituitary-adrenal axis function, where cortisol is likely playing a role in the development of chronic pain. These areas provide promising targets for interventions, the development of diagnostic biomarkers, and suggest that biological treatment strategies should focus on regulating the neuroinflammatory and stress responses in an effort to modulate and prevent the development of chronic pain.
Learn More >Cortical spreading depolarisation (CSD), the neural mechanism underlying migraine aura, may cause headache by sensitising the trigeminal system. Photophobia, the most bothersome accompanying symptom during migraine attacks, is more prevalent in migraine with aura than in migraine without aura. Whether CSD plays a role in developing photophobia remains unknown. Moreover, migraine-induced physical hypoactivity contributes to loss of productivity. We aimed to investigate the development of trigeminal sensitisation, photophobia and locomotive abnormality after KCl-induced CSD using 86 male C57BL/6 mice. Sham-operated mice were used as controls. We confirmed the presence of trigeminal sensitisation and photophobia at 24 h after CSD. CSD-subjected mice also exhibited significantly reduced locomotive activity in both light and dark zones. Hence, the CSD-induced hypomobility was likely to be independent of photophobia. The 5-HT agonist, sumatriptan, corrected all these CSD-induced abnormalities. Moreover, dose dependency was demonstrated in the ameliorating effect of the calcitonin gene-related peptide (CGRP) receptor antagonist, olcegepant, on these abnormalities. Sumatriptan and olcegepant improved mouse locomotion with therapeutic lags ranging from 20 to 30 min. Collectively, CSD caused trigeminal sensitisation, photophobia and hypomobility that persisted for at least 24 h by a mechanism involving the 5-HT and CGRP activity.
Learn More >Chronic migraine (CM) is a highly disabling primary headache. Botulinum toxin (onabotulinumtoxinA) is effective for treatment of CM, with ~ 50% of patients responding after 24 weeks. A response predictor would prevent unnecessary treatments. Inhibiting calcitonin gene related peptide (CGRP) release from trigeminal nociceptive fibres is one of the modes of acting discussed for onabotulinumtoxinA in CM. Therefore, we hypothesized that the response to triptans might predict response to onabotulinumtoxinA. Contrariwise, onabotulinumtoxinA treatment might affect triptan efficacy. 49 CM patients scheduled for their first onabotulinumtoxinA treatment were included. Before (T0) and three months after (T1) onabotulinumtoxinA treatment, patients rated triptan efficacy and indicated number of headache days/month. At T1, patients additionally rated onabotulinumtoxinA efficacy. Headache days/month were on average reduced by 7.1 ± 7.0 days from T0 to T1 (p < 0.001). Triptan efficacy ratings at T0 did not predict onabotulinumtoxinA efficacy ratings at T1 (p = 0.19) or reduction of headache days (p = 0.37). However, triptan efficacy significantly improved from T0 to T1 in onabotulinumtoxinA responders (p < 0.001) but not in non-responders (p = 1.00). Triptan efficacy did not predict response to onabotulinumtoxinA in CM. However, triptan efficacy increased after successful onabotulinumtoxinA treatment. This supports the hypothesis that efficacy of acute migraine treatment with triptans improves with effective migraine prophylaxis.
Learn More >There has been a substantial rise in the number of women pursuing careers in neurology. However, research has shown that women in neurology have high rates of burnout with gender disparities in burnout and attrition in the field. Recently, there was a call from the National Institutes of Health (NIH), including the National Institute of Neurological Disorders and Stroke (NINDS), asking for input on factors that may limit or discourage grant applications from women. As the recipients of the highly coveted NIH career mentored awards (K-awards) in headache medicine, we applaud the NIH for asking for gender specific feedback and for raising awareness of research showing that female faculty on the Research Track are at increased risk of departure. Using the NIH model for the Responsible Conduct of Research and the tenant of "Nurturing the Fertile Environment", we discuss specific challenges in academic research that may contribute to gender differences in neurology research success. While the rate of women conducting NIH-funded migraine research increased from 23 to 41% over the last 10 years, more women are currently in training compared to independence, with 6/6 of the NIH training grants but only 12/36 of the NIH Research-level grants, held by women in fiscal years 2017-2019. We suggest concrete solutions to these challenges to ensure the success of women in research reaching independence.
Learn More >Pain is one of the most common symptoms that people with cancer experience. Identification of demographic, physiologic, and behavioral correlates of pain among cancer survivors could help identify subgroups most in need of pain management.
Learn More >Little is understood about differences in resting neural activity among those with spinal cord injury (SCI)-related neuropathic pain. The purpose of this pilot study was to determine resting cerebral blood flow differences in persons with SCI-related neuropathic pain compared to healthy, pain-free able-bodied controls. Five persons with paraplegia and ten able-bodied participants were included in this study. Resting blood flow, as measured by a continuous arterial spin labeling (ASL) method of fMRI, was analyzed via statistical parametric mapping. Persons with SCI-related neuropathic pain had significantly lower resting blood flow in the cerebellum (Crus I/II), rostral ventromedial medulla and left insular cortex. In contrast, greater resting blood flow occurred in the medial orbitofrontal cortex among those with SCI-related neuropathic pain compared to controls. Differences in resting blood flow were observed among those with SCI-related pain, particularly in regions that may be involved in affective-motivational and cognitive-evaluative aspects of pain. Larger ASL studies in addition to functional connectivity studies using fMRI are needed to clarify unique neural patterns in this complex and often intractable form of pain.
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