Association of plasma tryptophan concentration with periaqueductal gray matter functional connectivity in migraine patients

Altered periaqueductal gray matter (PAG) functional connectivity contributes to brain hyperexcitability in migraine. Although tryptophan modulates neurotransmission in PAG projections through its metabolic pathways, the effect of plasma tryptophan on PAG functional connectivity (PAG-FC) in migraine has not been investigated yet. In this study, using a matched case-control design PAG-FC was measured during a resting-state functional magnetic resonance imaging session in migraine without aura patients (n = 27) and healthy controls (n = 27), and its relationship with plasma tryptophan concentration (TRP) was assessed. In addition, correlations of PAG-FC with age at migraine onset, migraine frequency, trait-anxiety and depressive symptoms were tested and the effect of TRP on these correlations was explored. Our results demonstrated that migraineurs had higher TRP compared to controls. In addition, altered PAG-FC in regions responsible for fear-cascade and pain modulation correlated with TRP only in migraineurs. There was no significant correlation in controls. It suggests increased sensitivity to TRP in migraine patients compared to controls. Trait-anxiety and depressive symptoms correlated with PAG-FC in migraine patients, and these correlations were modulated by TRP in regions responsible for emotional aspects of pain processing, but TRP did not interfere with processes that contribute to migraine attack generation or attack frequency.

Pediatric Neuromyelitis Optica Spectrum Disorder: Case Series and Literature Review

Neuromyelitis Optica Spectrum Disorder (NMOSD) is a central nervous system (CNS) inflammatory demyelinating disease characterized by recurrent inflammatory events that primarily involve optic nerves and the spinal cord, but also affect other regions of the CNS, including hypothalamus, area postrema and periaqueductal gray matter. The aquaporin-4 antibody (AQP4-IgG) is specific for NMOSD. Recently, myelin oligodendrocyte glycoprotein antibodies (MOG-IgG) have been found in a group of AQP4-IgG negative patients. NMOSD is rare among children and adolescents, but early diagnosis is important to start adequate therapy. In this report, we present cases of seven pediatric patients with NMOSD and we review the clinical and neuroimaging characteristics, diagnosis, and treatment of NMOSD in children.

Magnesium and Morphine in the Treatment of Chronic Neuropathic Pain–A Biomedical Mechanism of Action

The effectiveness of opioids in the treatment of neuropathic pain is limited. It was demonstrated that magnesium ions (Mg2+), physiological antagonists of N-methyl-D-aspartate receptor (NMDAR), increase opioid analgesia in chronic pain. Our study aimed to determine the molecular mechanism of this action. Early data indicate the cross-regulation of µ opioid receptor (MOR) and NMDAR in pain control. Morphine acting on MOR stimulates protein kinase C (PKC), while induction of NMDAR recruits protein kinase A (PKA), leading to a disruption of the MOR-NMDAR complex and promoting functional changes in receptors. The mechanical Randall-Selitto test was used to assess the effect of chronic Mg2+ and morphine cotreatment on streptozotocin-induced hyperalgesia in Wistar rats. The level of phosphorylated NMDAR NR1 subunit (pNR1) and phosphorylated MOR (pMOR) in the periaqueductal gray matter was determined with the Western blot method. The activity of PKA and PKC was examined by standard enzyme immunoassays. The experiments showed a reduction in hyperalgesia after coadministration of morphine (5 mg/kg intraperitoneally) and Mg2+ (40 mg/kg intraperitoneally). Mg2+ administered alone significantly decreased the level of pNR1, pMOR, and activity of both tested kinases. The results suggest that blocking NMDAR signaling by Mg2+ restores the MOR-NMDAR complex and thus enables morphine analgesia in neuropathic rats.

The Recovery of Cognitive and Affective Deficiencies Linked with Chronic Osteoarthritis Pain and Implicated Pathways by Slow-Releasing Hydrogen Sulfide Treatment

Chronic osteoarthritis pain is accompanied by several comorbidities whose treatment has not been completely resolved. The anti-inflammatory, analgesic, and antidepressant effects of slow-releasing hydrogen sulfide (H2S) donors during osteoarthritic pain have been shown, but their actions in the accompanying memory impairment and anxious-like behaviors have not yet been demonstrated. Using female mice with chronic osteoarthritic pain, the effects of natural, diallyl disulfide (DADS) or synthetic, morpholin-4-ium 4-methoxyphenyl(morpholino) phosphinodithioate dichloromethane complex (GYY4137) slow-releasing H2S donors, on associated cognitive and grip strength deficits and anxiodepressive-like behaviors, were assessed. Their effects on specific brain areas implicated in the modulation of pain and emotional responses were also determined. Results demonstrated an improvement in memory and grip strength deficits, as well as in the anxious-like behaviors associated with chronic pain in GYY4137 and/or DADS treated mice. The painkiller and antidepressant properties of both treatments were also established. Treatment with DADS and/or GYY4137 inhibited: oxidative stress in the amygdala; phosphoinositide 3-kinase overexpression in the amygdala, periaqueductal gray matter, and anterior cingulate cortex; protein kinase B activation in the amygdala and infralimbic cortex; up-regulation of inducible nitric oxide synthase in the amygdala, periaqueductal gray matter and infralimbic cortex and apoptotic responses in the amygdala. These results might explain the recovery of memory and grip strength and the inhibition of allodynia and associated anxiodepressive-like behaviors by these treatments. In conclusion, this study revealed new properties of slow-releasing H2S donors in cognitive impairment and affective disorders linked with chronic osteoarthritis pain and their effects on the central nervous system.