Central Pain Transmission Research Articles

Interictal plasma glutamate levels are elevated in individuals with episodic and chronic migraine

Glutamate is implicated in migraine pathogenesis including central sensitization and pain transmission. Altered plasma glutamate levels has been noted in migraine. Chronic migraine (CM) presented a higher degree of central sensitization and pain transmission than episodic migraine (EM). However, no study has evaluated plasma glutamate levels separately in EM and CM. This study aimed to assess plasma glutamate levels in EM and CM compared to controls. An enzyme-linked immunosorbent assay was used to assess plasma glutamate levels in females with EM (n = 98) and CM (n = 92) as well as controls (n = 50). Plasma glutamate levels in participants with EM (median and interquartile range, 49.73 [40.82–66.12] μmol/L, p < 0.001) and CM (58.70 [44.64–72.46] μmol/L, p < 0.001) were significantly higher than those in controls (38.79 [29.50–53.60] μmol/L). Glutamate levels were not significantly different between participants with EM and CM (p = 0.075). There was no significant association of plasma glutamate levels with headache frequency (exponential and 95% confidence interval, 1.285 [0.941–1.755]) and intensity (mild, 59.95 [59.95–59.95] μmol/L vs. moderate, 52.76 [40.83–106.89] μmol/L vs. severe, 55.16 [42.34–68.03] μmol/L, p = 0.472). The plasma glutamate level is a potential indicator for EM and CM.

Inflammatory cytokines in midbrain periaqueductal gray contribute to diabetic induced pain hypersensitivity through phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin signaling pathway.

BackgroundDiabetes-related neuropathic pain frequently occurs, and the underpinning mechanism remains elusive. The periaqueductal gray (PAG) exhibits descending inhibitory effects on central pain transmission. The current work aimed to examine whether inflammatory cytokines regulate mechanical allodynia and thermal hyperalgesia induced by diabetes through the phosphoinositide 3-kinase (PI3K)-mammalian target of rapamycin (mTOR) pathway in the PAG.MethodsStreptozotocin (STZ) was administered intraperitoneally to mimic allodynia and hyperalgesia evoked by diabetes in rats. Behavioral assays were carried out for determining mechanical pain and thermal hypersensitivity. Immunoblot and ELISA were performed to examine PAG protein amounts of interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α), as well as their corresponding receptors in STZ rats, and the expression of PI3K/protein kinase B (Akt)/mTOR signaling effectors.ResultsIncreased PAG p-PI3K/p-Akt/p-mTOR protein amounts were observed in STZ-induced animals, a PI3K-mTOR pathway inhibition in the PAG attenuated neuropathic pain responses. Moreover, the PAG concentrations of IL-1β, IL-6, and TNF-α and their receptors (namely, IL-1R, IL-6R, and tumor necrosis factor receptor [TNFR] subtype TNFR1, respectively) were increased in the STZ rats. Additionally, inhibiting IL-1R, IL-6R, and TNFR1 ameliorated mechanical allodynia and thermal hyperalgesia in STZ rats, alongside the downregulation of PI3K-mTOR signaling.ConclusionsOverall, the current study suggests that upregulated proinflammatory cytokines and their receptors in the PAG activate PI3K-mTOR signaling, thereby producing a de-inhibition effect on descending pathways in modulating pain transmission, and eventually contributing to neuropathic pain.

Inhibition of NADPH oxidase within midbrain periaqueductal gray decreases pain sensitivity in Parkinson's disease via GABAergic signaling pathway.

Hypersensitive pain response is observed in patients with Parkinson's disease (PD). However, the signal pathways leading to hyperalgesia still need to be clarified. Chronic oxidative stress is one of the hallmarks of PD pathophysiology. Since the midbrain periaqueductal gray (PAG) is an important component of the descending inhibitory pathway controlling on central pain transmission, we examined the role NADPH oxidase (NOX) of the PAG in regulating exaggerated pain evoked by PD. PD was induced by central microinjection of 6-hydroxydopamine to lesion the left medial forebrain bundle of rats. Then, Western Blot analysis and ELISA were used to determine NOXs and products of oxidative stress (i.e., 8-isoprostaglandin F2alpha and 8-hydroxy-2'-deoxyguanosine). Pain responses to mechanical and thermal stimulation were further examined in control rats and PD rats. In results, among the NOXs, protein expression of NOX4 in the PAG of PD rats was significantly upregulated, thereby the products of oxidative stress were increased. Blocking NOX4 pathway in the PAG attenuated mechanical and thermal pain responses in PD rats and this was accompanied with decreasing production of oxidative stress. In addition, inhibition of NOX4 largely restored the impaired GABA within the PAG. Stimulation of GABA receptors in the PAG of PD rats also blunted pain responses. In conclusions, NOX4 activation of oxidative stress in the PAG of PD rats is likely to impair the descending inhibitory GABAergic pathways in regulating pain transmission and thereby plays a role in the development of pain hypersensitivity in PD. Inhibition of NOX4 has beneficial effects on the exaggerated pain evoked by PD.

Comorbidity of Fibromyalgia in Primary Knee Osteoarthritis: Potential Impact on Functional Status and Quality of Life.

BackgroundKnee osteoarthritis (OA) is a painful condition with peripheral and central pain transmission. Fibromyalgia (FM) is the role model of central sensitization of pain perception.AimTo assess the frequency of FM in knee OA patients and evaluate the impact of FM on mental health and the quality of life in knee OA patients.Patients and MethodsA total of 121 female patients were recruited and divided into 3 groups: group I of 59 patients with knee OA only, group II of 32 patients with knee OA and FM, and group III of 30 FM patients. Patients underwent history taking, examination, investigations, and radiological evaluation of both knees. The assessment of visual analog scale (VAS), Pittsburgh Sleep Quality Index (PSQI), Pain Anxiety Symptom Scale Short Form 20 (PASS20), Beck Depression Inventory (BDI-II), and PCASEE questionnaire were done for all patients. Lequesne index of knee OA and radiological Kellgren and Lawrence score severity were done for all OA patients. Fibromyalgia Impact Questionnaire (FIQ) was assessed for all FM patients.ResultsFM was diagnosed in 35.5% of knee OA patients. Group II patients had higher VAS, PASS-20, PSQI, and lower quality of life than either groups I and III, elevated Lequesne index score than group I, significant correlation between VAS and BMI (p=0.002), Lequesne index score (p<0.001), PASS20 (p=0.006), BDI-II score (p=0.002), and FIQ (P<0.001), and a negative correlation was found between VAS and physical (p<0.001), anxiety (p=0.046), and social (p=0.026) QoL parameters. Univariable regression analysis showed a higher age, VAS, PSQI, PASS20, and FIQ were associated with lower QoL in group II. A higher PASS20 was the only predictor of lower QoL in multivariable analysis.ConclusionFibromyalgia coexists frequently in knee OA patients and has implications on their mental health, functional activity, and quality of life.

PGE2/EP4 receptor and TRPV1 channel are involved in repeated restraint stress-induced prolongation of sensitization pain evoked by subsequent PGE2 challenge

Prevalence of prior stressful experience is linked to high incidence of chronic pain. Stress, particularly repeated stress, is known to induce maladaptive neuroplasticity along peripheral and central pain transmission pathways. These maladaptive neuroplastic events facilitate sensitization of nociceptive neurons and transition from acute to chronic pain. Pro-inflammatory and pain mediators are involved in inducing neuroplasticity. Pain mediators such as prostaglandin E2 (PGE2), EP4 receptor and transient receptor potential vanilloid-1 (TRPV1) contributes to the genesis of chronic pain. In this study, we examined role of PGE2/EP4 signaling and TRPV1 signaling in repeated restraint stress-induced prolongation of sensitization pain, a model for transition from acute to chronic pain, in both in vivo and in vitro models. We found that pre-exposure to single restraint stress induced analgesia that masked sensitization pain evoked by subsequent PGE2 challenge. However, pre-exposure to 3d consecutive restraint stress not only prolonged sensitization pain, but also increased stress hormone corticosterone (CORT) in serum, COX2 levels in paw skin, EP4 and TRPV1 levels in dorsal root ganglion (DRG) and paw skin. Pre-exposure to CORT for 3d, not 1d, also prolonged sensitization pain evoked by PGE2. Co-injection of glucocorticoid receptor (GR) antagonist RU486, COX2 inhibitor NS-398, EP4 receptor antagonist L161, 982 or TRPV1 antagonist capsazepine prevented 3d restraint stress prolonged sensitization pain evoked by PGE2. In DRG cultures, CORT increased EP4 and TRPV1 protein levels through GR activation. These data suggest that PGE2/EP4 signaling and TRPV1 signaling in peripheral pain pathway contributes to repeated stress-predisposed transition from acute to chronic pain.

PGE2/EP4 receptor and TRPV1 channel are involved in repeated restraint stress-induced prolongation of sensitization pain evoked by subsequent PGE2 challenge

Prevalence of prior stressful experience is linked to high incidence of chronic pain. Stress, particularly repeated stress, is known to induce maladaptive neuroplasticity along peripheral and central pain transmission pathways. These maladaptive neuroplastic events facilitate sensitization of nociceptive neurons and transition from acute to chronic pain. Pro-inflammatory and pain mediators are involved in inducing neuroplasticity. Pain mediators such as prostaglandin E2 (PGE2), EP4 receptor and transient receptor potential vanilloid-1 (TRPV1) contribute to the genesis of chronic pain. In this study, we examined the role of PGE2/EP4 signaling and TRPV1 signaling in repeated restraint stress-induced prolongation of sensitization pain, a model for transition from acute to chronic pain, in both in vivo and in vitro models. We found that pre-exposure to single restraint stress induced analgesia that masked sensitization pain evoked by subsequent PGE2 challenge. However, pre-exposure to 3d consecutive restraint stress not only prolonged sensitization pain, but also increased stress hormone corticosterone (CORT) in serum, COX2 levels in paw skin, and EP4 and TRPV1 levels in dorsal root ganglion (DRG) and paw skin. Pre-exposure to CORT for 3d, not 1d, also prolonged sensitization pain evoked by PGE2. Co-injection of glucocorticoid receptor (GR) antagonist RU486, COX2 inhibitor NS-398, EP4 receptor antagonist L161,982 or TRPV1 antagonist capsazepine prevented 3d restraint stress prolonged sensitization pain evoked by PGE2. In DRG cultures, CORT increased EP4 and TRPV1 protein levels through GR activation. These data suggest that PGE2/EP4 signaling and TRPV1 signaling in peripheral pain pathway contribute to repeated stress-predisposed transition from acute to chronic pain.

Neuroinflammation and central PI3K/Akt/mTOR signal pathway contribute to bone cancer pain.

BackgroundPain is one of the most common and distressing symptoms suffered by patients with progression of cancer; however, the mechanisms responsible for hyperalgesia are not well understood. Since the midbrain periaqueductal gray is an important component of the descending inhibitory pathway controlling on central pain transmission, in this study, we examined the role for pro-inflammatory cytokines of the periaqueductal gray in regulating mechanical and thermal hyperalgesia evoked by bone cancer via phosphatidylinositide 3-kinase (PI3K)–mammalian target of rapamycin (mTOR) signals.MethodsBreast sarcocarcinoma Walker 256 cells were implanted into the tibia bone cavity of rats to induce mechanical and thermal hyperalgesia. Western blot analysis and ELISA were used to examine PI3K/protein kinase B (Akt)/mTOR and pro-inflammatory cytokine receptors and the levels of interleukin (IL)-1β, IL-6, and tumor necrosis factor-alpha (TNF-α).ResultsProtein expression levels of p-PI3K/p-Akt/p-mTOR were amplified in the periaqueductal gray of bone cancer rats, and blocking PI3K–mTOR pathways in the periaqueductal gray attenuated hyperalgesia responses. In addition, IL-1β, IL-6, and TNF-α were elevated in the periaqueductal gray of bone cancer rats, and expression of their respective receptors (namely, IL-1R, IL-6R, and tumor necrosis factor receptor (TNFR) subtype TNFR1) was upregulated. Inhibition of IL-1R, IL-6R, and TNFR1 alleviated mechanical and thermal hyperalgesia in bone cancer rats, accompanied with downregulated PI3K–mTOR.ConclusionsOur data suggest that upregulation of pro-inflammatory cytokine signal in the periaqueductal gray of cancer rats amplifies PI3K–mTOR signal in this brain region and alters the descending pathways in regulating pain transmission, and this thereby contributes to the development of bone cancer-induced pain.

Acquisition of analgesic properties by the cholecystokinin (CCK)/CCK2 receptor system within the amygdala in a persistent inflammatory pain condition

Pain is associated with negative emotions such as anxiety, but the underlying neurocircuitry and modulators of the association of pain and anxiety remain unclear. The neuropeptide cholecystokinin (CCK) has both pronociceptive and anxiogenic properties, so we explored the role of CCK in anxiety and nociception in the central amygdala (CeA), a key area in control of emotions and descending pain pathways. Local infusion of CCK into the CeA of control rats increased anxiety, as measured in the light-dark box test, but had no effect on mechanical sensitivity. By contrast, intra-CeA CCK infusion 4 days after Complete Freund's Adjuvant (CFA) injection into the hindpaw resulted in analgesia, but also in loss of its anxiogenic capacity. Inflammatory conditions induced changes in the CeA CCK signaling system with an increase of CCK immunoreactivity and a decrease in CCK1, but not CCK2, receptor mRNA. In CFA rats, patch-clamp experiments revealed that CCK infusion increased CeA neuron excitability. It also partially blocked the discharge of wide dynamic range neurons in the dorsal spinal cord. These effects of CCK on CeA and spinal neurons in CFA rats were mimicked by the specific CCK2 receptor agonist, gastrin. This analgesic effect was likely mediated by identified CeA neurons projecting to the periaqueductal gray matter that express CCK receptors. Together, our data demonstrate that intra-CeA CCK infusion activated a descending CCK2 receptor-dependent pathway that inhibited spinal neuron discharge. Thus, persistent pain induces a functional switch to a newly identified analgesic capacity of CCK in the amygdala, indicating central emotion-related circuit controls pain transmission in spinal cord.

Participation of pro-inflammatory cytokines in neuropathic pain evoked by chemotherapeutic oxaliplatin via central GABAergic pathway.

BackgroundNeuropathic pain is observed in patients as chemotherapeutic oxaliplatin is used to treat metastatic digestive tumors; however, the mechanisms responsible for hyperalgesia are not well understood. Chronic neuroinflammation is one of the hallmarks of pathophysiology of neuropathic pain. Since the midbrain periaqueductal gray is an important component of the descending inhibitory pathway controlling on central pain transmission, we examined the role for pro-inflammatory cytokines system of the periaqueductal gray in regulating mechanical hyperalgesia and cold hypersensitivity evoked by oxaliplatin.MethodsNeuropathic pain was induced by intraperitoneal injection of oxaliplatin in rats. ELISA and western blot analysis were used to examine pro-inflammatory cytokine levels and their receptors expression.ResultsIL-1β, IL-6, and TNF-α were elevated within the periaqueductal gray of oxaliplatin rats. Protein expression of IL-1β, IL-6, and TNF-α receptors (namely, IL-1R, IL-6R, and TNFR subtype TNFR1) in the plasma membrane periaqueductal gray of oxaliplatin rats was upregulated, whereas the total expression of pro-inflammatory cytokine receptors was not altered. In oxaliplatin rats, impaired inhibitory gamma-aminobutyric acid within the periaqueductal gray was accompanied with decreases in withdrawal thresholds to mechanical stimulus and % time spent on the cold plate. Our data further showed that the concentrations of gamma-aminobutyric acid were largely restored by blocking those pro-inflammatory cytokine receptors in periaqueductal gray of oxaliplatin rats; and mechanical hyperalgesia and cold hypersensitivity evoked by oxaliplatin were attenuated. Stimulation of gamma-aminobutyric acid receptors in the periaqueductal gray also blunted neuropathic pain in oxaliplatin rats.ConclusionsOur data suggest that the upregulation of pro-inflammatory cytokines and membrane pro-inflammatory cytokine receptor in the periaqueductal gray of oxaliplatin rats is likely to impair the descending inhibitory pathways in regulating pain transmission and thereby contributes to the development of neuropathic pain after application of chemotherapeutic oxaliplatin.

Improving Cellular Uptake and Endosomal Targeting of Neurokinin 1 Receptor Antagonists

IntroG protein‐coupled receptors (GPCRs) are cell‐surface sensors that control most pathophysiological processes. Following stimulation, many activated receptors redistribute to endosomes and evidence suggests that endosome‐localized receptors generate signals that are distinct from cell surface signaling outputs. Importantly, these endosomal signals underlie physiologically relevant cellular processes. We have recently observed that Substance P‐mediated endosomal signalling from the Neurokinin 1 Receptor (NK1R) is associated with central pain transmission and hence, the selective inhibition of NK1R within endosomes could be therapeutically advantageous.Methods and ResultsWe have synthesized a series of membrane anchored drug conjugates including Cyanine‐5 fluorophore conjugated to spantide (Span‐Cy5), cholestanol (Cy5‐Chol), spantide and cholestanol (Cy5‐Span‐Chol), or a PEG‐ethyl ester control (Cy5‐EE). Cellular uptake, membrane association and ligand‐receptor interactions were determined by live cell confocal microscopy and fluorescence correlation spectroscopy. Biological activity of these constructs was determined by ERK functional assays. These data demonstrate that cholestanol membrane anchors enhance cellular uptake, membrane‐localized drug concentrations and endosomal distribution of fluorescently labelled, lipid‐conjugated compounds. Furthermore, these compounds can interact with the NK1R and demonstrate improved analgesic potential in pre‐clinical pain models, relative to their non‐targeted counterparts.Support or Funding InformationFunding support for the National Health and Medical Research Institute and the ARC Centre of Excellence for Bio‐Nano Science and Technology

Contribution of Pro-inflammatory Cytokine Signaling within Midbrain Periaqueductal Gray to Pain Sensitivity in Parkinson's Disease via GABAergic Pathway.

Hypersensitive pain response is often observed in patients with Parkinson's disease (PD); however, the mechanisms responsible for hyperalgesia are not well understood. Chronic neuroinflammation is one of the hallmarks of PD pathophysiology. Since the midbrain periaqueductal gray (PAG) is an important component of the descending inhibitory pathway controlling on central pain transmission, we examined the role for pro-inflammatory cytokines (PICs) system of PAG in regulating exaggerated pain evoked by PD. We used a rat model of PD to perform the experimental protocols. PD was induced by microinjection of 6-hydroxydopamine to lesion the left medial forebrain bundle. Pain responses to mechanical and thermal stimulation were first examined in control rats and PD rats. Then, ELISA and Western Blot analysis were used to determine PIC levels and their receptors expression. Protein expression of IL-1β, IL-6, and TNF-α receptors (namely, IL-1R, IL-6R, and TNFR subtype TNFR1) in the plasma membrane PAG of PD rats was upregulated, whereas the total expression of PIC receptors was not significantly altered. The ratio of membrane protein and total protein (IL-1R, IL-6R, and TNFR1) was 1.48 ± 0.15, 1.59 ± 0.18, and 1.67 ± 0.16 in PAG of PD rats (P < 0.05 vs. their respective controls). This was accompanied with increases of PICs of PAG and decreases of GABA (623 ± 21 ng/mg in control rats and 418 ± 18 ng/mg in PD rats; P < 0.05 vs. control rats) and withdrawal thresholds to mechanical and thermal stimuli. Our data further showed that the concentrations of GABA and withdrawal thresholds were largely restored by blocking those PIC receptors in PAG of PD rats. Stimulation of GABA receptors in PAG of PD rats also blunted a decrease in withdrawal thresholds. Our data suggest that upregulation of the membrane PIC receptor in the PAG of PD rats is likely to impair the descending inhibitory pathways in regulating pain transmission and thereby plays a role in the development of hypersensitive pain response in PD.

Nociceptive transmission and modulation via P2X receptors in central pain syndrome.

Painful sensations are some of the most frequent complaints of patients who are admitted to local medical clinics. Persistent pain varies according to its causes, often resulting from local tissue damage or inflammation. Central somatosensory pathway lesions that are not adequately relieved can consequently cause central pain syndrome or central neuropathic pain. Research on the molecular mechanisms that underlie this pathogenesis is important for treating such pain. To date, evidence suggests the involvement of ion channels, including adenosine triphosphate (ATP)-gated cation channel P2X receptors, in central nervous system pain transmission and persistent modulation upon and following the occurrence of neuropathic pain. Several P2X receptor subtypes, including P2X2, P2X3, P2X4, and P2X7, have been shown to play diverse roles in the pathogenesis of central pain including the mediation of fast transmission in the peripheral nervous system and modulation of neuronal activity in the central nervous system. This review article highlights the role of the P2X family of ATP receptors in the pathogenesis of central neuropathic pain and pain transmission. We discuss basic research that may be translated to clinical application, suggesting that P2X receptors may be treatment targets for central pain syndrome.

Contributions of purinergic P2X3 receptors within the midbrain periaqueductal gray to diabetes-induced neuropathic pain.

Hyperalgesia and allodynia are commonly observed in patients with diabetic neuropathy. The mechanisms responsible for neuropathic pain are not well understood. Thus, in this study, we examined the role played by purinergic P2X3 receptors of the midbrain periaqueductal gray (PAG) in modulating diabetes-induced neuropathic pain because this brain region is an important component of the descending inhibitory system to control central pain transmission. Our results showed that mechanical withdrawal thresholds were significantly increased by stimulation of P2X3 receptors in the dorsolateral PAG of rats (n = 12, P < 0.05 vs. vehicle control) using α,β-methylene-ATP (α,β-meATP, a P2X3 receptor agonist). In addition, diabetes was induced by an intraperitoneal injection of streptozotocin (STZ) in rats, and mechanical allodynia was observed 3 weeks after STZ administration. Notably, the excitatory effects of P2X3 stimulation on mechanical withdrawal thresholds were significantly blunted in STZ-induced diabetic rats (n = 12, P < 0.05 vs. control animals) as compared with control rats (n = 12). Furthermore, the protein expression of P2X3 receptors in the plasma membrane of the dorsolateral PAG of STZ-treated rats was significantly decreased (n = 10, P < 0.05 vs. control animals) compared to that in control rats (n = 8), whereas the total expression of P2X3 receptors was not significantly altered. Overall, data of our current study suggest that a decrease in the membrane expression of P2X3 receptors in the PAG of diabetic rats is likely to impair the descending inhibitory system in modulating pain transmission and thereby contributes to the development of mechanical allodynia in diabetes.

Are Peripheral Pain Generators Important in Fibromyalgia and Chronic Widespread Pain?

Fibromyalgia (FM) is a chronic widespread pain syndrome (CWPS) that is generally considered to be the result of a dysfunctional central pain modulating system. It is thought to importantly involve the descending pain inhibitory system. FM is known to be associated with multimodal hypersensitivity: mechanical, thermal, visual, and auditory. It is associated with a variety of comorbid conditions including irritable bowel syndrome, painful bladder, migraine headache, and temporo-mandibular joint syndrome. The relationship of the comorbid conditions to FM has not been clear. They can be considered to be the result of hyper-effective ascending central pain transmission resulting from deficient descending pain inhibition, or they can be considered as clinical entities in themselves, whose importance in FM lies in their acting as peripheral pain generators that enhance or initiate central sensitization, thereby contributing to chronic widespread pain. There may, of course, be some truth in both of these concepts. The presence of peripheral pain generators that lead to central sensitization initiating or maintaining CWPS or FM remains controversial, however. This question is addressed in a masterful study by Albrecht et al. ⇓ …

Stellate Ganglion Block as an Early Intervention in Sympathetically Maintained Headache and Orofacial Pain Caused by Temporal Arteritis

We report a case of temporal arteritis with a sympathetic component in the orofacial region, which responded to stellate ganglion blocks (SGBs). An 81-year-old woman with limited mouth opening and pain upon chewing was referred to the Orofacial Pain Clinic at Nihon University Dental Hospital. The patient also presented with blurred vision and a burning sensation on the right side of her face. On clinical examination, the temporal artery was tender to palpation, and there was increased sensitivity in the temporal region bilaterally. The patient reported jaw pain and limited mouth opening. Laboratory examination showed elevations in erythrocyte sedimentation rate and C-reactive protein. The burning sensation was due to a sympathetic component, and SGBs substantially reduced both the burning sensation and right temporal pain. Blocking the sympathetic chain on the ipsilateral side also improved jaw movement. The patient was referred to a rheumatologist, after which she was admitted to hospital with a tentative diagnosis of temporal arteritis. Treatment with oral prednisone 30 mg daily was initiated, and the dose was tapered as her symptoms resolved. The reason for the gradual pain relief after SGB is unclear, but we believe it was effective for ischemia in temporal arteritis because it led to dilation of affected arteries or suppression of inflammation/edema of the vascular wall. This case demonstrates that SGB may relieve pain related to temporal arteritis and sympathetically maintained headache and orofacial pain by reducing noxious stimulation peripherally and decreasing central pain transmission centrally.

Impaired nocifensive behaviours and mechanical hyperalgesia, but enhanced thermal allodynia in pituitary adenylate cyclase-activating polypeptide deficient mice

Pituitary adenylate cyclase-activating polypeptide-38 (PACAP-38) and its receptors (PAC1 and VPAC) have been shown in the spinal dorsal horn, dorsal root ganglia and sensory nerve terminals. Data concerning the role of PACAP in central pain transmission are controversial and we have recently published its divergent peripheral effects on nociceptive processes. The aim of the present study was to investigate acute somatic and visceral nocifensive behaviours, partial sciatic nerve ligation-evoked chronic neuropathic, as well as resiniferatoxin-induced inflammatory thermal and mechanical hyperalgesia in PACAP deficient (PACAP(-/-)) mice to elucidate its overall function in pain transmission. Neuronal activation was investigated with c-Fos immunohistochemistry. Paw lickings in the early (0-5 min) and late (20-45 min) phases of the formalin test were markedly reduced in PACAP(-/-) mice. Acetic acid-evoked abdominal contractions referring to acute visceral chemonociception was also significantly attenuated in PACAP knockout animals. In both models, the excitatory role of PACAP was supported by markedly greater c-Fos expression in the periaqueductal grey and the somatosensory cortex. In PACAP-deficient animals neuropathic mechanical hyperalgesia was absent, while c-Fos immunopositivity 20 days after the operation was significantly higher. In this chronic model, these neurons are likely to indicate the activation of secondary inhibitory pathways. Intraplantarly injected resiniferatoxin-evoked mechanical hyperalgesia involving both peripheral and central processes was decreased, but thermal allodynia mediated by only peripheral mechanisms was increased in PACAP(-/-) mice. These data clearly demonstrate an overall excitatory role of PACAP in pain transmission originating from both exteroceptive and interoceptive areas, it is also involved in central sensitization. This can be explained by the signal transduction mechanisms of its identified receptors, both PAC1 and VPAC activation leads to neuronal excitation. In contrast, it is an inhibitory mediator at the level of the peripheral sensory nerve endings and decreases their sensitization to heat with presently unknown mechanisms.

Current progress in the pharmacological therapy of fibromyalgia

Fibromyalgia (FM) is a chronic musculoskeletal pain disorder often associated with fatigue, dyscognition, and sleep disturbances. Recent research advances highlight a critical role for aberrant central pain processing in FM, and, consistent with these data, the first three drugs approved by the FDA for FM over the past 2 years have a predominantly central mode of action. The first drug, pregabalin, may counteract central pain transmission by inhibiting presynaptic release of excitatory neurotransmitters, including substance P and glutamate. The serotonin-norepinephrine reuptake inhibitors duloxetine and milnacipran have been approved more recently and are believed to reduce pain by increasing serotonin and norepinephrine concentrations in descending inhibitory pain pathways. Agents with multiple other mechanisms of action are in development and promise an assortment of therapeutic options for this complex disorder in the near future.

Role of pituitary adenylate-cyclase activating polypeptide in mouse models of nocifensive behaviours and hyperalgesia

Event Abstract Back to Event Role of pituitary adenylate-cyclase activating polypeptide in mouse models of nocifensive behaviours and hyperalgesia Zsuzsanna Helyes1*, Katalin Sándor1, Viktoria Kormos1, Balint Botz1, Andras Imreh1, Kata Bolcskei2, Janos Szolcsanyi1, Shintani Norihito3, Hitoshi Hashimoto3, Akemichi Baba3 and Dóra Reglődi4 1 University of Pecs, Department of Pharmacology and Pharmacotherapy, Hungary 2 University of Pécs and Gedeon-Richter Ltd.; , Hungary 3 Medical School of Osaka University, Japan 4 University of Pécs, Department of Anatomy, Hungary Pituitary adenylate cyclase-activating polypeptide-38 (PACAP-38) and its receptors (PAC1 and VPAC) are present in the spinal dorsal horn, dorsal root ganglia, and both central and peripheral terminals of capsaicin-sensitive sensory neurones. Data concerning the role of PACAP in central pain transmission are contraversial and we have recently published its divergent peripheral effects on nociceptive processes. Our aim was to investigate acute somatic and visceral nocifensive behaviors, partial sciatic nerve ligation-evoked neuropathic as well as resiniferatoxin-induced inflammatory mechanical and thermal hyperalgesia in PACAP deficient (PACAP-/-) mice to elucidate its overall function in pain transmission. The number of paw lickings in the early and late phases of the formalin test reflecting acute somatic chemonocifensive behavior and acute inflammatory nociception, respectively, was markedly diminished in PACAP-/- mice. Acetic acid-evoked abdominal contractions referring to acute visceral chemonociception was also significantly attenuated in the PACAP-/- group. Neuropathic mechanical hyperalgesia was absent in PACAP-deficient animals. Resiniferatoxin-evoked mechanical hyperalgesia which involves both peripheral and central mechanisms was decreased, but thermal hyperalgesia mediated by only peripheral mechanisms was increased in PACAP-/- mice. These data demonstrate that the overall role of PACAP in pain transmission originating from both exteroceptive and interoceptive areas is excitatory, it is involved in central sensitization. The signal transduction mechanisms of its identified receptors leading to neuronal excitation, explain these findings. In contrast, it has an inhibitory action on the peripheral sensory nerve endings and decreases their sensitization to heat. This suggests the existence of a potential, presently unknown, inhibitory mechanism in peripheral nerve terminals. Hungarian Grants K72592, K73044, RET-008/2005, ETT-06-348/2006, ETT-06-284/2006 and Janos Bolyai Postdoctoral Research Fellowship. PACAP+/- mice were kindly provided by Dr. Nobuhisa Iwata, RIKEN Brain Science Institute, Saitama, Japan. Conference: 12th Meeting of the Hungarian Neuroscience Society, Budapest, Hungary, 22 Jan - 24 Jan, 2009. Presentation Type: Poster Presentation Topic: Pathophysiology and neurology - non-degenerative disorders Citation: Helyes Z, Sándor K, Kormos V, Botz B, Imreh A, Bolcskei K, Szolcsanyi J, Norihito S, Hashimoto H, Baba A and Reglődi D (2009). Role of pituitary adenylate-cyclase activating polypeptide in mouse models of nocifensive behaviours and hyperalgesia. Front. Syst. Neurosci. Conference Abstract: 12th Meeting of the Hungarian Neuroscience Society. doi: 10.3389/conf.neuro.01.2009.04.031 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 26 Feb 2009; Published Online: 26 Feb 2009. * Correspondence: Zsuzsanna Helyes, University of Pecs, Department of Pharmacology and Pharmacotherapy, Pecs, Hungary, zsuzsanna.helyes@aok.pte.hu Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Zsuzsanna Helyes Katalin Sándor Viktoria Kormos Balint Botz Andras Imreh Kata Bolcskei Janos Szolcsanyi Shintani Norihito Hitoshi Hashimoto Akemichi Baba Dóra Reglődi Google Zsuzsanna Helyes Katalin Sándor Viktoria Kormos Balint Botz Andras Imreh Kata Bolcskei Janos Szolcsanyi Shintani Norihito Hitoshi Hashimoto Akemichi Baba Dóra Reglődi Google Scholar Zsuzsanna Helyes Katalin Sándor Viktoria Kormos Balint Botz Andras Imreh Kata Bolcskei Janos Szolcsanyi Shintani Norihito Hitoshi Hashimoto Akemichi Baba Dóra Reglődi PubMed Zsuzsanna Helyes Katalin Sándor Viktoria Kormos Balint Botz Andras Imreh Kata Bolcskei Janos Szolcsanyi Shintani Norihito Hitoshi Hashimoto Akemichi Baba Dóra Reglődi Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Divergent peripheral effects of pituitary adenylate cyclase-activating polypeptide-38 on nociception in rats and mice

Pituitary adenylate cyclase-activating polypeptide-38 (PACAP-38) and its receptors have been shown in the spinal dorsal horn, on capsaicin-sensitive sensory neurons and inflammatory cells. The role of PACAP in central pain transmission is controversial, and no data are available on its function in peripheral nociception. Therefore, the aim of the present study was to analyze the effects of locally or systemically administered PACAP-38 on nocifensive behaviors, inflammatory/neuropathic hyperalgesia and afferent firing. Intraplantar PACAP-38 (0.2nmol) injection inhibited carrageenan-evoked inflammatory mechanical allodynia, mild heat injury-induced thermal hyperalgesia, as well as nocifensive behaviors in the early and late phases of the formalin test in rats. However, the above dose did not alter basal mechanical or heat thresholds. In mice, PACAP-38 (0.2nmol/kg s.c.) significantly diminished acetic acid-induced abdominal contractions, but exerted no effect on sciatic nerve ligation-induced neuropathic mechanical hyperalgesia. In contrast, local PACAP-38 injection markedly increased rotation-induced afferent firing in the inflamed rat knee joint clearly demonstrating a peripheral sensitization in this organ. These actions were blocked by VPAC1/VPAC2 receptor antagonist pretreatment, but were not altered by PAC1 receptor antagonism. This paper presents the first data for the peripheral actions of PACAP-38 on nociceptive transmission mediated by VPAC receptors. These effects seem to be divergent depending on the mechanisms of nociceptor activation and the targets of PACAP actions. In acute somatic and visceral inflammatory pain models, PACAP exerts anti-nociceptive, anti-hyperalgesic and anti-allodynic effects. It has no significant peripheral role in traumatic mononeuropathy, but induces mechanical sensitization of knee joint primary afferents.

Tomographie par émission de positons dans la migraine

Due to technical constraints and randomness of migraine attacks, studies using PET are scarce. Nevertheless, these studies have given new insights into migraine pathogenesis. One of the main facts revealed by PET studies is that posterior cerebral hypoperfusion accompanying migraine auras could also be present in migraine attacks without aura. This hypoperfusion is probably due to an increase of intrinsic vasoconstrictive tone in the cerebral circulation. Using PET within 6 hours after the onset of a spontaneous migraine attack, significant activations of brainstem (midbrain and pons) and of hypothalamus, persisting after headache relief by sumatriptan have been shown. These structures could play the role of migraine attack generators, modulating intrinsic vascular tone and central pain transmission.