Direct Evidence for the Ongoing Brain Activation by Enhanced Dynorphinergic System in the Spinal Cord under Inflammatory Noxious Stimuli

Taketa, Yasuko; Niikura, Keiichi; Kobayashi, Yasuhisa; Furuya, Masaharu; Shimizu, Tadayori; Narita, Michiko; Imai, Shoichi; Kuzumaki, Naoko; Maitani, Yoshie; Yamazaki, Mitsuaki; Inada, Eiichi; Iseki, Masako; Suzuki, Tsutomu; Narita, Minoru

doi:10.1097/aln.0b013e3181ca31d9

Cited by 8 publications

(8 citation statements)

References 52 publications

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“…Reports of specific drivers of neuromodulators (e.g., dyorphin) have been employed in knockout vs. control mice in response to inflammatory stimuli (complete Freunds adjuvant) (Taketa et al, 2010); no activation was observed in regions such as the cingulate, somatosensory and insular cortices or thalamus in prodynorphin knockout mice. Other fMRI visceral pain studies have included those in acute pancreatitis (see Figure 3A) (Westlund et al, 2009), investigating the effects of a mu agonist (morphine) and mu antagonist (naloxone) and following a peripheral pain stimulus (intraplantar formalin).…”

Section: Preclinical Functional Imaging Of Painmentioning

confidence: 99%

CNS animal fMRI in pain and analgesia

Borsook

Becerra

2011

Neuroscience & Biobehavioral Reviews

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Animal imaging of brain systems offers exciting opportunities to better understand the neurobiology of pain and analgesia. Overall functional studies have lagged behind human studies as a result of technical issues including the use of anesthesia. Now that many of these issues have been overcome including the possibility of imaging awake animals, there are new opportunities to study whole brain systems neurobiology of acute and chronic pain as well as analgesic effects on brain systems de novo (using pharmacological MRI) or testing in animal models of pain. Understanding brain networks in these areas may provide new insights into translational science, and use neural networks as a "language of translation" between preclinical to clinical models. In this review we evaluate the role of functional and anatomical imaging in furthering our understanding in pain and analgesia.

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Section: Preclinical Functional Imaging Of Painmentioning

confidence: 99%

CNS animal fMRI in pain and analgesia

Borsook

Becerra

2011

Neuroscience & Biobehavioral Reviews

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“…Both KOR and PDYN KO mice are viable, with reported phenotypic effects on neural function such as enhancement of pain perception. 1,[27][28][29] Vascular phenotype, however, has not been investigated in either of these KO mice. Both KOR and PDYN KO mice showed a greater density of CD31 ϩ vessels in the periphery of EϪ10.5 embryonic brains (Figure 6B-C).…”

Section: Kor or Dynorphin Ko Mice Show Increased Vascular Formation Imentioning

confidence: 99%

“…Prodynorphin (PDYN) gene-KO mice (The Jackson Laboratory), 27,28 KOR gene-KO mice (The Jackson Laboratory), 29 or C57BL/6J mice (CLEA Japan Inc) were used. Mice were allowed to mate naturally at night.…”

Section: Micementioning

confidence: 99%

The κ opioid system regulates endothelial cell differentiation and pathfinding in vascular development

Yamamizu

Furuta

Katayama

et al. 2011

Blood

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The opioid system (opioid peptides and receptors) regulates a variety of neurophysiologic functions, including pain control. Here we show novel roles of the opioid system in vascular development. IntroductionOpioids are defined by their ability to bind to and influence opioid receptors on cell membranes. Three opioid receptors, , ␦, and (MOR, DOR, and KOR), are inhibitory G (Gi) protein-coupled receptors through which endogenous opioids (endorphins, enkephalins, and dynorphins) regulate physiologic functions, such as pain regulation, emotional tone, and reward circuitry. 1 These opioid receptors are the principle physiologic target for most clinically important opioid analgesics, such as morphine. Opioid systems are mainly present in neural tissue and could be involved in neurogenesis during brain development. 2,3 We previously showed that DOR, but not MOR or KOR, plays a crucial role in neurogenesis and neuroprotection in neural stem cells obtained from embryonic C3H mouse forebrain. 4 In recent studies that used embryonic stem (ES) cells, MOR and KOR were shown to promote neural progenitor differentiation and regulate cell specification from neural progenitors. 5,6 Moreover, KOR is highly expressed in human neural precursor cells and functions during neurogenesis in the fetal brain. 7 These results indicate that the opioid systems are involved in neurogenesis from neural stem and progenitor cells.Although endogenous opioids were first characterized in the brain, these opioid systems are found both in neural (brain and spinal cord) and extraneural tissues (ganglia, gut, spleen, stomach, lung, pancreas, liver, heart, blood, and blood vessels). Opioids and opioid receptors were reported to exist in blood vessels in the later stage rat embryo (embryonic day [E]Ϫ16) through adult. 8,9 The addition of opioid peptides inhibited angiogenesis in a chick chorioallantoic membrane model 10 and DNA synthesis in rat vascular walls. 8 In the adult, the endogenous opioid system has been shown to be active in hemodynamic and cardiovascular responses, such as hemorrhagic shock, sepsis, and trauma. 11 The selective opioid receptor agonist U-50,488H has beneficial effects on vascular injury after spinal cord trauma by improving vascular permeability and edema. 12 These findings suggest that the opioid system plays an important role in vascular functions though its physiologic roles and molecular mechanisms remain largely unknown.VEGF/VEGF receptor-2 (fetal liver kinase 1; Flk1) signaling is a key regulator of vascular development during embryogenesis. A VEGF coreceptor, Neuropilin1 (NRP1), is largely coexpressed with Flk1 in vascular progenitors and forms a specific and sensitive receptor for VEGF 164 , an isoform of VEGF. 13,14 The Flk1-VEGF 164 -NRP1 complex potently enhances Flk1 signaling in vascular development. 13 NRP1 is also expressed in particular classes of developing neurons and functions as a receptor for class 3 semaphorins by forming a heterodimer with plexins. [15][16][17] PlexinD1 and semaphorin regulate not onl...

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“…Under these circumstances, 'ON'-RVM neurons do not respond to inhibitory signals from PAG, whereas they are highly stimulated by ascending inputs (Figure 4) 86,92,93 that release glutamate, SP and dynorphin over thalamic and brainstem neurons including 'ON'-RVM cells. [84][85][86][87][88][89][90][91][92][93][94][95][96] In summary, all these neurotransmitters released by nociceptive ascending neurons over 'ON'-RVM neurons cause their hyperexcitability (Figure 4). 97 Neuropathic and inflammatory pain also causes changes in PAG neurons.…”

Section: Molecular Neuroplasticity Of the Descending Inhibitory Pain mentioning

confidence: 99%

Neuroplasticity of ascending and descending pathways after somatosensory system injury: reviewing knowledge to identify neuropathic pain therapeutic targets

et al. 2016

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Study design: This is a narrative review of the literature. Objectives: This review aims to be useful in identifying therapeutic targets. It focuses on the molecular and biochemical neuroplasticity changes that occur in the somatosensory system, including ascending and descending pathways, during the development of neuropathic pain. Furthermore, it highlights the latest experimental strategies, based on the changes reported in the damaged nociceptive neurons during neuropathic pain states. Setting: This study was conducted in Girona, Catalonia, Spain. Methods: A MEDLINE search was performed using the following terms: descending pain pathways; ascending pain pathways; central sensitization; molecular pain; and neuropathic pain pharmacological treatment. Results and conclusion: Neuropathic pain triggered by traumatic lesions leads to sensitization and hyperexcitability of nociceptors and projection neurons of the dorsal horn, a strengthening in the descendent excitatory pathway and an inhibition of the descending inhibitory pathway of pain. These functional events are associated with molecular plastic changes such as overexpression of voltagegated ion channels, algogen-sensitive receptors and synthesis of several neurotransmitters. Molecular studies on the plastic changes in the nociceptive somatosensory system enable the development of new pharmacological treatments against neuropathic pain, with higher specificity and effectiveness than classical drug treatments. Although research efforts have already focused on these aspects, additional research may be necessary to further explore the potential therapeutic targets in neuropathic pain involved in the neuroplasticity changes of neuropathological pathways from the injured somatosensory system.

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Direct Evidence for the Ongoing Brain Activation by Enhanced Dynorphinergic System in the Spinal Cord under Inflammatory Noxious Stimuli

Abstract: These findings indicate that spinally released dynorphin A (1-17) by noxious stimuli leads to the direct activation of ascending pain transmission.

Cited by 8 publications

References 52 publications

CNS animal fMRI in pain and analgesia

CNS animal fMRI in pain and analgesia

The κ opioid system regulates endothelial cell differentiation and pathfinding in vascular development

Neuroplasticity of ascending and descending pathways after somatosensory system injury: reviewing knowledge to identify neuropathic pain therapeutic targets

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