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Migraine is the seventh most disabling disorder globally, with prevalence of 11.7% worldwide. One of the prevailing mechanisms is the activation of the trigeminovascular system, and calcitonin gene-related peptide (CGRP) is an important therapeutic target for migraine in this system. Recent studies suggested an emerging role of pituitary adenylate cyclase-activating peptide (PACAP) in migraine. However, the relation between CGRP and PACAP and the role of PACAP in migraine remain undefined. In this study, we established a novel repetitive (one, three, and seven days) electrical stimulation model by stimulating dura mater in conscious rats. Then, we determined expression patterns in the trigeminal ganglion and the trigeminal nucleus caudalis of the trigeminovascular system. Electrical stimulation decreased facial mechanical thresholds, and the order of sensitivity was as follows: vibrissal pad >inner canthus >outer canthus (P < 0.001). The electrical stimulation group exhibited head-turning and head-flicks (P < 0.05) nociceptive behaviors. Importantly, electrical stimulation increased the expressions of CGRP, PACAP, and the PACAP-preferring type 1 (PAC1) receptor in both trigeminal ganglion and trigeminal nucleus caudalis (P < 0.05). The expressions of two vasoactive intestinal peptide (VIP)-shared type 2 (VPAC1 and VPAC2) receptors were increased in the trigeminal ganglion, whereas in the trigeminal nucleus caudalis, their increases were peaked on Day 3 and then decreased by Day 7. PACAP was colocalized with NEUronal Nuclei (NeuN), PAC1, and CGRP in both trigeminal ganglion and the trigeminal nucleus caudalis. Our results demonstrate that the repetitive electrical stimulation model can simulate the allodynia during the migraine chronification, and PACAP plays a role in the pathogenesis of migraine potentially via PAC1 receptor.
Learn More >The neuropeptide of calcitonin gene-related peptide (CGRP) plays critical roles in chronic pain, especially in migraine. Immunohistochemistry and in situ hybridization studies have shown that CGRP and its receptors are expressed in cortical areas including pain perception related prefrontal anterior cingulate cortex (ACC). However, less information is available for the functional roles of CGRP in cortical regions such as the ACC. Recent studies have consistently demonstrated that long-term potentiation (LTP) is a key cellular mechanism for chronic pain in the ACC. In the present study, we used 64-electrode array field recording system to investigate the effect of CGRP on excitatory transmission in the ACC. We found that CGRP induced potentiation of synaptic transmission in a dose-dependently manner (1, 10, 50, and 100 nM). CGRP also recruited inactive circuit in the ACC. An application of the calcitonin receptor-like receptor antagonist CGRP8-37 blocked CGRP-induced chemical LTP and the recruitment of inactive channels. CGRP-induced LTP was also blocked by NMDA receptor antagonist AP-5. Consistently, application of CGRP increased NMDA receptor mediated excitatory postsynaptic currents (EPSCs). Finally, we found that CGRP-induced LTP requires activation of calcium-stimulated adenylyl cyclase subtype 1 (AC1) and PKA. Genetic deletion of AC1 using AC1-/- mice, an AC1 inhibitor NB001 or a PKA inhibitor KT5720 all reduced or blocked CGRP induced potentiation. Our results provide direct evidence that CGRP may contribute to synaptic potentiation in important physiological and pathological conditions in the ACC, an AC1 inhibitor NB001 may be beneficial for the treatment of chronic headache.
Learn More >Features suggestive of neuropathic pain (NP) have been described in RA in addition to nociceptive pain. We aimed to determine the clinical predictors of NP in RA patients and study its association with radiographic structural damage.
Learn More >Vincristine, oxaliplatin, and cisplatin are commonly prescribed chemotherapeutic agents for the treatment of many tumors. However, a main side-effect is chemotherapy-induced peripheral neuropathy (CIPN), which may lead to changes in chemotherapeutic treatment. Although symptoms associated with CIPN are recapitulated by mouse models, there is limited knowledge of how these drugs affect the expression of genes in sensory neurons. The present study carried out a transcriptomic analysis of dorsal root ganglia (DRG) following vincristine, oxaliplatin, and cisplatin treatment with a view to gain insight into the comparative pathophysiological mechanisms of CIPN. RNA-Seq revealed 368, 295 and 256 differential expressed genes (DEGs) induced by treatment with vincristine, oxaliplatin and cisplatin, respectively and only five shared genes were dysregulated in all three groups. Cell type enrichment analysis and gene set enrichment analysis showed predominant effects on genes associated with the immune system after treatment with vincristine, while oxaliplatin treatment affected mainly neuronal genes. Treatment with cisplatin resulted in a mixed gene expression signature. Perspective: These results provide insight into the recruitment of immune responses to DRG and indicate enhanced neuro-inflammatory processes following administration of vincristine, oxaliplatin, and cisplatin. These gene expression signatures may provide insight into novel drug targets for treatment of CIPN.
Learn More >Patients with cancer, especially breast, prostate, and lung cancer, commonly experience bone metastases that are difficult to manage and are associated with bone cancer pain (BCP). Amitriptyline is often used to treat chronic pain, such as neuropathic pain. In the present study, the effects of amitriptyline on the mechanical withdrawal threshold (MWT) and its underlying mechanisms were evaluated in rat models of BCP. Walker 256 rat mammary gland carcinoma cells were injected into the bone marrow cavity of the right tibia of rats to provoke BCP. Then, amitriptyline was intraperitoneally administered twice daily from fifth day after the operation. Rats with bone cancer showed an apparent decline in the MWT at day 11 after Walker 256 cells inoculation. The levels of the glutamate transporter GLAST in the spinal cord dorsal horn decreased remarkably, and the concentration of the excitatory amino acid (EAA) glutamate (Glu) in the cerebrospinal fluid (CSF) increased substantially. Amitriptyline injection could prevent the decline of MWT in BCP rats. In addition, GLAST was upregulated on the glial cell surface, and Glu levels were reduced in the CSF. However, amitriptyline injection could not prevent the BCP-induced reduction in GLAST in the glial cell cytosol, it further downregulated cytosolic GLAST. Amitriptyline had no significant effect on GLAST mRNA expression, and BCP-invoked PKA/PKC upregulation was prevented. Taken together, these results suggest that the intraperitoneal injection of amitriptyline can prevent the decrease of MWT in BCP rats, the underlying mechanisms may be associated with the inhibition of PKA/PKC expression, thus promoting GLAST trafficking onto the glial cell surface and reducing EAA concentrations in the CSF.
Learn More >This study aims to (1) examine the temporal influence of peer victimization on mood, sleep quality, pain, and activity limitations in clinical and community samples of youth, and (2) test mood and sleep as mediators of peer victimization-pain pathways. One hundred fifty-six adolescents (n=74 chronic pain group) completed a week of online diary monitoring assessing their daily peer victimization experiences, negative mood, sleep quality, pain intensity, and pain-related activity limitations. In multilevel models controlling for group status, person-mean peer victimization (averaged across days) significantly predicted worse mood, pain, and activity limitations (all ps < .01) while daily victimization predicted worse mood (p < .05). Results from within-person mediation indicated a significant indirect effect of daily peer victimization on next-day activity limitations, through daily negative mood. Results from between-person mediation indicated that negative mood significantly mediated the relation between peer victimization and pain and the relation between peer victimization and activity limitations. Peer victimization is associated with negative health indicators in clinical and community samples of youth and may exert its influence on pain and pain-related activity limitations through negative mood. PERSPECTIVE: This article examines the temporal influence of peer victimization on pain in adolescents with and without chronic pain, and examines mood and sleep quality as mechanisms linking victimization to pain. This information may be useful for pain prevention researchers as well as providers who assess and treat pain in childhood.
Learn More >The periaqueductal gray (PAG) is a significant modulator of both analgesic and fear behaviors in both humans and rodents, but the underlying circuitry responsible for these two phenotypes is incompletely understood. Importantly, it is not known if there is a way to produce analgesia without anxiety by targeting the PAG, as modulation of glutamate or GABA neurons in this area initiates both antinociceptive and anxiogenic behavior. While dopamine (DA) neurons in the ventrolateral PAG (vlPAG)/dorsal raphe display a supraspinal antinociceptive effect, their influence on anxiety and fear are unknown. Using DAT-cre and Vglut2-cre male mice, we introduced designer receptors exclusively activated by designer drugs (DREADD) to DA and glutamate neurons within the vlPAG using viral-mediated delivery and found that levels of analgesia were significant and quantitatively similar when DA and glutamate neurons were selectively stimulated. Activation of glutamatergic neurons, however, reliably produced higher indices of anxiety, with increased freezing time and more time spent in the safety of a dark enclosure. In contrast, animals in which PAG/dorsal raphe DA neurons were stimulated failed to show fear behaviors. DA-mediated antinociception was inhibitable by haloperidol and was sufficient to prevent persistent inflammatory pain induced by carrageenan. In summary, only activation of DA neurons in the PAG/dorsal raphe produced profound analgesia without signs of anxiety, indicating that PAG/dorsal raphe DA neurons are an important target involved in analgesia that may lead to new treatments for pain.
Learn More >The purpose of this article was to examine age-related changes in conditioned pain modulation (CPM) and temporal summation of pain (TS) using meta-analytic techniques. Five electronic databases were searched for studies that compared measures of CPM and TS between healthy, chronic pain-free younger, middle-aged, and older adults. Eleven studies were included in the final review for TS and 11 studies were included in the review of CPM. The results suggested a moderate magnitude of difference in TS between younger adults and middle-aged/older adults, with the older cohorts exhibiting enhanced TS of pain. Considerable variability existed in the magnitude of the effects sizes, which was likely due to the different experimental methodology used across studies (i.e., inter-stimulus interval, stimulus type, body location). In regards to CPM, the data revealed a large magnitude of difference between younger and older adults, with younger adults exhibiting more efficient pain inhibition. Differences in CPM between middle-aged and older adults were minimal. The magnitude of pain inhibition during CPM in older adults may depend on the use of concurrent vs. non-concurrent protocols. In summary, the data provided strong quantitative evidence of a general age-related decline in endogenous pain modulatory function as measured by TS and CPM. PERSPECTIVE: This review compared conditioned pain modulation and temporal summation of pain between younger, middle-aged, and older adults. These findings enhance our understanding of the decline in endogenous pain modulatory function associated with normal aging.
Learn More >The development of multitarget opioid drugs has emerged as an attractive therapeutic strategy to eliminate opioid-related side effects. Our previous study developed a series of opioid and neuropeptide FF (NPFF) pharmacophore-containing chimeric peptides, including DN-9 (Tyr-D.Ala-Gly-NMe.Phe-Gly-Pro-Gln-Arg-Phe-NH), which produced potent nontolerance forming analgesia at the supraspinal level. In the present study, the antinociceptive effects of DN-9 in a series of preclinical pain models and the potential side-effects were investigated at the spinal level in mice. In the tail-flick test, intrathecal injection of DN-9 produced potent analgesia with an ED value at 1.33 pmol, and the spinal antinociception of DN-9 was mainly mediated by μ- and κ-opioid receptors. In addition, DN-9-induced spinal antinociception was augmented by the NPFF receptors antagonist. Furthermore, DN-9 could decrease both the frequency and amplitude of sEPSCs in lamina IIo neurons of the spinal cord, which were mediated by opioid receptors. In contrast to morphine, chronic intrathecal treatments with DN-9 did not induce analgesic tolerance, c-Fos expression or microglial activation. Intrathecal injection of DN-9 showed potent analgesia with antinociceptive ED values between 0.66 and 55.04 pmol in different pain models, including the formalin test, acetic acid-induced writhing test, carrageen-induced inflammatory pain and neuropathic pain. Moreover, DN-9 did not show side effects in locomotor function and coordination, gastrointestinal transit inhibition, the cardiovascular system, and body temperature regulation at antinociceptive doses. Taken together, the present study showed DN-9 produced effective, nontolerance forming analgesia with reduced side effects at the spinal level. DN-9 might be a promising compound for developing multifunctional opioid analgesics with limited adverse effects. Perspective: This article presents the potent and nontolerance forming analgesia effects of DN-9 in a series of preclinical pain models with less opioid related adverse effects at the spinal level in mice. This study also demonstrates that DN-9 has translational potential into an intrathecal analgesic.
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