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Migraine is one of the most disabling disorders worldwide but the underlying mechanisms are poorly understood. Stress is consistently reported as a common trigger of migraine attacks. Here we show that repeated stress in mice causes migraine-like behaviors that are responsive to a migraine therapeutic. Adult female and male mice were exposed to 2 hours of restraint stress for 3 consecutive days, after which they demonstrated facial mechanical hypersensitivity and facial grimace responses that were resolved by 14 days post-stress. Hypersensitivity or grimace was not observed in either control animals or those stressed for only 1 day. Following return to baseline, the NO-donor sodium nitroprusside (SNP; 0.1 mg/kg) elicited mechanical hypersensitivity in stressed but not in control animals, demonstrating the presence of hyperalgesic priming. This suggests the presence of a migraine-like state, since NO-donors are reliable triggers of attacks in migraine patients but not controls. The stress paradigm also caused priming responses to dural pH 7.0 treatment. The presence of this primed state after stress is not permanent as it was no longer present at 35 days post-stress. Finally, mice received either the CGRP monoclonal antibody ALD405 (10 mg/kg) 24 hours prior to SNP or a co-injection of sumatriptan (0.6 mg/kg). ALD405, but not sumatriptan, blocked the facial hypersensitivity due to SNP. This stress paradigm in mice and the subsequent primed state caused by stress, allow further preclinical investigation of mechanisms contributing to migraine, particularly those caused by common triggers of attacks.
Functional restoration programs (FRPs) are integrative programs to improve function in chronic low back pain (cLBP). They are costly and time-consuming. The aim was to assess the effectiveness of a condensed FRP (CFRP) for patients with cLBP in professional activity.
Neurotensin (NT) exerts naloxone-insensitive antinociceptive action through its binding to both NTS and NTS receptors and NT analogs provide stronger pain relief than morphine on a molecular basis. Here, we examined the analgesic/adverse effect profile of a new NT(8-13) derivative denoted JMV2009, in which the Pro residue was substituted by a silicon-containing unnatural amino acid silaproline. We first report the synthesis and in vitro characterization (receptor-binding affinity, functional activity and stability) of JMV2009. We next examined its analgesic activity in a battery of acute, tonic and chronic pain models. We finally evaluated its ability to induce adverse effects associated with chronic opioid use, such as constipation and analgesic tolerance or related to NTS activation, like hypothermia. In in vitro assays, JMV2009 exhibited high binding affinity for both NTS and NTS, improved proteolytic resistance as well as agonistic activities similar to NT, inducing sustained activation of p42/p44 MAPK and receptor internalization. Intrathecal injection of JMV2009 produced dose-dependent antinociceptive responses in the tail-flick test and almost completely abolished the nociceptive-related behaviors induced by chemical somatic and visceral noxious stimuli. Likewise, increasing doses of JMV2009 significantly reduced tactile allodynia and weight bearing deficits in nerve-injured rats. Importantly, repeated agonist treatment did not result in the development of analgesic tolerance. Furthermore, JMV2009 did not cause constipation and was ineffective in inducing hypothermia. These findings suggest that NT drugs can act as an effective opioid-free medication for the management of pain or can serve as adjuvant analgesics to reduce the opioid adverse effects.
Novel synthetic opioids are appearing in recreational drug markets worldwide as adulterants in heroin or ingredients in counterfeit analgesic medications. 3,4-Dichloro-N-[(1R,2R)-2-(dimethylamino)cyclohexyl]-N-methylbenzamide (U-47700) is an example of a non-fentanyl synthetic opioid linked to overdose deaths. Here, we examined the pharmacodynamics and pharmacokinetics of U-47700 in rats. Male Sprague-Dawley rats were fitted with intravenous (i.v.) catheters and subcutaneous (s.c.) temperature transponders under ketamine/xylazine anesthesia. One week later, rats received s.c. injections of U-47700 HCl (0.3, 1.0 or 3.0 mg/kg) or saline, and blood samples (0.3 mL) were withdrawn via i.v. catheters at 15, 30, 60, 120, 240, 480 min post-injection. Pharmacodynamic effects were assessed at each blood withdrawal, and plasma was assayed for U-47700 and its metabolites by liquid chromatography tandem mass spectrometry. U-47700 induced dose-related increases in hot plate latency (ED = 0.5 mg/kg) and catalepsy (ED = 1.7 mg/kg), while the 3.0 mg/kg dose also caused hypothermia. Plasma levels of U-47700 rose linearly as dose increased, with maximal concentration (C) achieved by 15-38 min. C values for N-desmethyl-U-47700 and N,N-didesmethyl-U-47700 were delayed but reached levels in the same range as the parent compound. Pharmacodynamic effects were correlated with plasma U-47700 and its N-desmethyl metabolite. Using radioligand binding assays, U-47700 displayed high affinity for μ-opioid receptors (Ki = 11.1 nM) whereas metabolites were more than 18-fold weaker. Our data reveal that U-47700 induces typical μ-opioid effects which are related to plasma concentrations of the parent compound. Given its high potency, U-47700 poses substantial risk to humans who are inadvertently exposed to the drug.
Fibromyalgia is a chronic disorder characterized by widespread pain and by several non-pain symptoms. Autoimmunity, small fiber neuropathy and neuroinflammation have been suggested to be involved in the pathogenesis of the disease. We have investigated the gene expression profile in peripheral blood mononuclear cells obtained from ten patients and ten healthy subjects. Of the 545,500 transcripts analyzed, 1673 resulted modulated in fibromyalgic patients. The majority of these genes are involved in biological processes and pathways linked to the clinical manifestations of the disease. Moreover, genes involved in immunological pathways connected to interleukin-17 and to Type I interferon signatures were also modulated, suggesting that autoimmunity plays a role in the disease. We then aimed at identifying differentially expressed Long non-coding RNAs (LncRNAs) functionally connected to modulated genes both directly and via microRNA targeting. Only two LncRNAs of the 298 found modulated in patients, were able to target the most highly connected genes in the fibromyalgia interactome, suggesting their involvement in crucial gene regulation. Our gene expression data were confirmed by real time PCR, by autoantibody testing, detection of soluble mediators and Th-17 polarization in a validation cohort of 50 patients. Our results indicate that genetic and epigenetic mechanisms as well as autoimmunity play a pivotal role in the pathogenesis of fibromyalgia.
We previously reported that neuropathic pain was associated with smaller posterior cingulate cortical (PCC) volumes, suggesting that a smaller/dysfunctional PCC may contribute to development of pain via impaired mind wandering. A gap in our previous report was lack of evidence for a mechanism for the genesis of PCC atrophy in HIV peripheral neuropathy. Here we investigate if volumetric differences in the subcortex for those with neuropathic paresthesia may contribute to smaller PCC volumes, potentially through deafferentation of ascending white matter tracts resulting from peripheral nerve damage in HIV neuropathy. Since neuropathic pain and paresthesia are highly correlated, statistical decomposition was used to separate pain and paresthesia symptoms to determine which regions of brain atrophy are associated with both pain and paresthesia and which are associated separately with pain or paresthesia. HIV+ individuals (N = 233) with and without paresthesia in a multisite study underwent structural brain magnetic resonance imaging. Voxel-based morphometry and a segmentation/registration tool were used to investigate regional brain volume changes associated with paresthesia. Analysis of decomposed variables found that smaller midbrain and thalamus volumes were associated with paresthesia rather than pain. However, atrophy in the PCC was related to both pain and paresthesia. Peak thalamic atrophy (p = 0.004; MNI x = - 14, y = - 24, z = - 2) for more severe paresthesia was in a region with reciprocal connections with the PCC. This provides initial evidence that smaller PCC volumes in HIV peripheral neuropathy are related to ascending white matter deafferentation caused by small fiber damage observed in HIV peripheral neuropathy.
Migraine is a leading cause of disability worldwide, but it is still underdiagnosed and undertreated. Research on the pathophysiology of this neurological disease led to the discovery that calcitonin gene-related peptide (CGRP) is a key neuropeptide involved in pain signaling during a migraine attack. CGRP-mediated neuronal sensitization and glutamate-based second- and third-order neuronal signaling may be an important component involved in migraine pain. The activation of several serotonergic receptor subtypes can block the release of CGRP, other neuropeptides, and neurotransmitters, and can relieve the symptoms of migraine. Triptans were the first therapeutics developed for the treatment of migraine, working through serotonin 5-HT receptors. The discovery that the serotonin 1F (5-HT) receptor was expressed in the human trigeminal ganglion suggested that this receptor subtype may have a role in the treatment of migraine. The 5-HT receptor is found on terminals and cell bodies of trigeminal ganglion neurons and can modulate the release of CGRP from these nerves. Unlike 5-HT receptors, the activation of 5-HT receptors does not cause vasoconstriction.The potency of different serotonergic agonists towards 5-HT was correlated in an animal model of migraine (dural plasma protein extravasation model) leading to the development of lasmiditan. Lasmiditan is a newly approved acute treatment for migraine in the United States and is a lipophilic, highly selective 5-HT agonist that can cross the blood-brain barrier and act at peripheral nervous system (PNS) and central nervous system (CNS) sites.Lasmiditan activation of CNS-located 5-HT receptors (e.g., in the trigeminal nucleus caudalis) could potentially block the release of CGRP and the neurotransmitter glutamate, thus preventing and possibly reversing the development of central sensitization. Activation of 5-HT receptors in the thalamus can block secondary central sensitization of this region, which is associated with progression of migraine and extracephalic cutaneous allodynia. The 5-HT receptors are also elements of descending pain modulation, presenting another site where lasmiditan may alleviate migraine. There is emerging evidence that mitochondrial dysfunction might be implicated in the pathophysiology of migraine, and that 5-HT receptors can promote mitochondrial biogenesis. While the exact mechanism is unknown, evidence suggests that lasmiditan can alleviate migraine through 5-HT agonist activity that leads to inhibition of neuropeptide and neurotransmitter release and inhibition of PNS trigeminovascular and CNS pain signaling pathways.
Mu-opioid receptors (MORs) are crucial for analgesia by both exogenous and endogenous opioids. However, the distinct mechanisms underlying these two types of opioid analgesia remains largely unknown. Here, we demonstrate that analgesic effects of exogenous and endogenous opioids on inflammatory pain are mediated by MORs expressed in distinct subpopulations of neurons in mouse. We found that the exogenous opioid-induced analgesia of inflammatory pain is mediated by MORs in Vglut2 glutamatergic but not GABAergic neurons. In contrast, analgesia by endogenous opioids is mediated by MORs in GABAergic rather than Vglut2 glutamatergic neurons. Furthermore, MORs expressed at the spinal level is mainly involved in the analgesic effect of morphine in acute pain, but not in endogenous opioid analgesia during chronic inflammatory pain. Thus, our study revealed distinct mechanisms underlying analgesia by exogenous and endogenous opioids, and laid the foundation for further dissecting the circuit mechanism underlying opioid analgesia.
Phosphorylation of the 5' cap-binding protein eIF4E by MAPK interacting kinases MNK1/2 is important for nociceptor sensitization and the development of chronic pain. IL-6 induced DRG nociceptor excitability is attenuated in mice lacking eIF4E phosphorylation, in MNK1/2 mice and by the nonselective MNK1/2 inhibitor cercosporamide. Here, we sought to better understand the neurophysiological mechanisms underlying how IL-6 causes nociceptor excitability via MNK-eIF4E signaling using the highly selective MNK inhibitor eFT508 . Dorsal root ganglion (DRG) neurons were cultured from male and female ICR mice, 4-7 weeks old. DRG cultures were treated with vehicle, IL-6, eFT508 (pretreat) followed by IL-6 or eFT508 alone. Whole-cell patch clamp recordings were done on small diameter neurons (20-30 pF) to measure membrane excitability in response to ramp depolarization. One hr IL-6 treatment resulted in increased action potential firing compared to vehicle at all ramp intensities, an effect that was blocked by pretreatment with eFT508. Basic membrane properties, including resting membrane potential, input resistance and rheobase, were similar across groups. Latency to the first action potential in the ramp protocol was lower in the IL-6 group, and rescued by eFT508 pretreatment. We also found that the amplitudes of T-type voltage-gated calcium channels (VGCCs) were increased in the DRG following IL-6 treatment, but not in the eFT508 co-treatment group. Our findings are consistent with a model wherein MNK-eIF4E signaling controls the translation of signaling factors that regulate T-type VGCCs in response to IL-6 treatment. Inhibition of MNK with eFT508 disrupts these events, thereby preventing nociceptor hyperexcitability.
Many patients' chronic musculoskeletal pain is strongly influenced by central nervous system processes such as sensitization or amplification. Education about pain neuroscience can change patients' beliefs but has less consistent effects on pain outcomes. Patients may have greater clinical benefits if the educational intervention is personalized, and they evaluate various psychosocial risk factors with respect to their pain. We developed and tested a brief, internet-based Pain Psychology and Neuroscience (PPN) self-evaluation intervention.