Complete inhibition of purinoceptor agonist-induced nociception by spinorphin, but not by morphine

Ueda, Hiroshi; Matsunaga, Shinobu; Inoue, Makoto; Yamamoto, Yasutake; Hazato, Tadahiko

doi:10.1016/s0196-9781(00)00262-x

Cited by 38 publications

(34 citation statements)

References 18 publications

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“…The maximal effect occurred with approximately 10 fmol of peptide. By comparison, 1-10 fmol of nociceptin͞orphanin FQ, 2 pmol of bradykinin, and 10 pmol of substance P cause maximal responses in this pain assay (19,34). In situ hybridization histochemistry studies have shown that the PTH2 receptor is present at low levels on vascular endothelium (6, 7), so we cannot be absolutely certain that the effect of TIP39 results from activation of PTH2 receptors on the peripheral processes of sensory neurons.…”

Section: Resultsmentioning

confidence: 88%

Anatomical and physiological evidence for involvement of tuberoinfundibular peptide of 39 residues in nociception

Dobolyi

Ueda

Uchida

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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110

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The parathyroid hormone 2 (PTH2) receptor's anatomical distribution suggests that, among other functions, it may be involved in modulation of nociception. We localized PTH2 receptor protein to spinal cord lamina II and showed that it is synthesized by subpopulations of primary sensory neurons and intrinsic spinal cord dorsal horn neurons. Tuberoinfundibular peptide of 39 residues (TIP39) selectively activates the PTH2 receptor. Intraplantar microinjection of TIP39 caused a paw-withdrawal response and intrathecal injection caused scratching, biting, and licking, a nocifensive response. Intrathecal administration of a TIP39 antibody decreased sensitivity in tail-flick and paw-pressure assays. Intrathecal administration of TIP39 potentiated responses in these assays. We determined the sequence of TIP39's precursor and found that mRNA encoding TIP39 and TIP39-like immunoreactivity is concentrated in two brainstem areas, the subparafascicular area and the caudal paralemniscal nucleus. Cells in these areas project to the superficial dorsal horn of the spinal cord. Our data suggest that TIP39 released from supraspinal fibers potentiates aspects of nociception within the spinal cord.

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Section: Resultsmentioning

confidence: 88%

Anatomical and physiological evidence for involvement of tuberoinfundibular peptide of 39 residues in nociception

Dobolyi

Ueda

Uchida

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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110

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“…Currently, there is only limited information regarding the endogenous substances that may be released into the spinal cord following P2X 3 /P2X 2/3 receptor activation for in vivo models of altered nociception. While it is appreciated that both peripheral and spinal application of ATP can trigger the release of glutamate into the dorsal horn (Gu & MacDermott, 1997;Tsuda et al, 1999a;Wismer et al, 2003), other endogenous agents such as substance P, nitric oxide, GABA and opioids may also be involved (Bland-Ward & Humphrey, 1997;Fukuhara et al, 2000;Hugel & Schlichter, 2000;Ueda et al, 2000;Nakatsuka et al, 2001). Thus, even though a clear role for P2X 3 /P2X 2/3 receptors has been demonstrated in many models of pathological nociception, the exact mechanisms for action in each of the models must be further explored.…”

Section: S Mcgaraughty Et Almentioning

confidence: 99%

Effects of A‐317491, a novel and selective P2X₃/P2X_2/3 receptor antagonist, on neuropathic, inflammatory and chemogenic nociception following intrathecal and intraplantar administration

McGaraughty

Wismer

Zhu

et al. 2003

British J Pharmacology

169

129

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1 We have recently reported that systemic delivery of A-317491, the first non-nucleotide antagonist that has high affinity and selectivity for blocking P2X 3 homomeric and P2X 2/3 heteromeric channels, is antinociceptive in rat models of chronic inflammatory and neuropathic pain. In an effort to further evaluate the role of P2X 3 /P2X 2/3 receptors in nociceptive transmission, A-317491 was administered either intrathecally or into the hindpaw of a rat in several models of acute and chronic nociception. 2 Intraplantar (ED 50 ¼ 300 nmol) and intrathecal (ED 50 ¼ 30 nmol) injections of A-317491 produced dose-related antinociception in the CFA model of chronic thermal hyperalgesia. Administration of A-317491 by either route was much less effective to reduce thermal hyperalgesia in the carrageenan model of acute inflammatory hyperalgesia. 3 Intrathecal, but not intraplantar, delivery of A-317491 attenuated mechanical allodynia in both the chronic constriction injury and L5-L6 nerve ligation models of neuropathy (ED 50 ¼ 10 nmol for both models). Intrathecal injections of A-317491 did not impede locomotor performance. 4 Both routes of injection were effective in reducing the number of nocifensive events triggered by the injection of formalin into a hindpaw. Nocifensive behaviors were significantly reduced in both the first and second phases of the formalin assay (intrathecal ED 50 ¼ 10 nmol, intraplantar ED 50 4300 nmol). Nocifensive behaviors induced by the P2X receptor agonist a,b-meATP were also significantly reduced by intraplantar injection of A-317491. 5 These data indicate that both spinal and peripheral P2X 3 /P2X 2/3 receptors have significant contributions to nociception in several animal models of nerve or tissue injury. Intrathecal administration of A-317491 appears to be more effective than intraplantar administration to reduce tactile allodynia following peripheral nerve injury.

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“…Tynorphin (Val-Val-Tyr-Pro-Trp), a synthetic, truncated form of spinorphin, is a highly specific inhibitor of DPP III and was shown to induce an even more potent antinociceptive effect (14,16). An important role of DPP III in the mammalian pain modulatory system is supported by several recent findings: low levels of DPP III activity were detected in the cerebrospinal fluid of individuals suffering from acute pain (17); DPP III exhibits high in vitro affinity toward the important neuropeptides endomorphin-1 and endomorphin-2 (18); and neuroanatomical studies localized rat DPP III in the superficial laminae of the dorsal horn, where enkephalin-synthesizing neurons and high concentrations of endomorphin-2 are found (19,20).…”

mentioning

confidence: 99%

“…Because of a different mode of action compared with morphine, spinorphin is an analgesic, potentially useful for pain treatment in morphine-resistant cases (14). This opioid peptide was also shown to be a potent and selective antagonist of the receptor P2X3, which is involved in pain signaling in chronic inflammatory nociception and neuropathic pain due to nerve injury (15).…”

mentioning

confidence: 99%

Entropy-driven binding of opioid peptides induces a large domain motion in human dipeptidyl peptidase III

Bezerra

Dobrovetsky

Viertlmayr

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

161

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Opioid peptides are involved in various essential physiological processes, most notably nociception. Dipeptidyl peptidase III (DPP III) is one of the most important enkephalin-degrading enzymes associated with the mammalian pain modulatory system. Here we describe the X-ray structures of human DPP III and its complex with the opioid peptide tynorphin, which rationalize the enzyme's substrate specificity and reveal an exceptionally large domain motion upon ligand binding. Microcalorimetric analyses point at an entropy-dominated process, with the release of water molecules from the binding cleft ("entropy reservoir") as the major thermodynamic driving force. Our results provide the basis for the design of specific inhibitors that enable the elucidation of the exact role of DPP III and the exploration of its potential as a target of pain intervention strategies.isothermal titration calorimetry | metallopeptidase | peptide binding | X-ray crystallography T he endogenous opioid system, composed of opioid peptides and their receptors, modulates a large number of physiological processes, such as endocrine and immune function, gastrointestinal motility, respiration, reward, stress, complex social behavior (e.g., sexual activity), vulnerability to drug addiction, and most notably the procession and transmission of pain stimuli (nociception) (1, 2). Two major types of endogenous opioid peptides are those containing enkephalin sequences at the N terminus (TyrGly-Gly-Phe-Met/Leu) (3) and, more recently identified, endomorphins 1 and 2 (Tyr-Pro-Trp/Phe-Phe-NH 2 ) (4, 5). Knowledge and control over synthesis and degradation pathways of this class of molecules is prerequisite for the development of new therapies that target pertinent physiological processes.Dipeptidyl peptidase III (DPP III), also known as enkephalinase B, is an enkephalin-degrading enzyme that cleaves dipeptides sequentially from the N termini of substrates (6). All DPP IIIs described thus far contain the unique zinc-binding motif HEXXGH characteristic of metallopeptidase family M49 (7). Enzymes from several human and animal tissues, as well as from lower eukaryotes, were purified and biochemically characterized (8, 9). DPP III is largely found as a cytosolic protein, although membrane association in rat brain and Drosophila melanogaster has been described (10, 11). The 3D structure of the yeast ortholog has recently been determined, revealing a unique protein fold with two lobes forming a wide-open substrate-binding cleft (12). The lack of structural information on peptide complexes, however, left the question of substrate specificity largely unanswered.DPP III purified from monkey brain microsomes is strongly inhibited by the neuropeptide spinorphin (Leu-Val-Val-Tyr-ProTrp-Thr), an endogenous factor isolated from bovine spinal cord that also inhibits other enkephalin-degrading enzymes, such as neutral endopeptidase (NEP, neprilysin), aminopeptidase, and angiotensin-converting enzyme (13). Because of a different mode of action compared with morphine, spinorp...

show abstract

Complete inhibition of purinoceptor agonist-induced nociception by spinorphin, but not by morphine

Cited by 38 publications

References 18 publications

Anatomical and physiological evidence for involvement of tuberoinfundibular peptide of 39 residues in nociception

Anatomical and physiological evidence for involvement of tuberoinfundibular peptide of 39 residues in nociception

Effects of A‐317491, a novel and selective P2X₃/P2X_2/3 receptor antagonist, on neuropathic, inflammatory and chemogenic nociception following intrathecal and intraplantar administration

Entropy-driven binding of opioid peptides induces a large domain motion in human dipeptidyl peptidase III

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Complete inhibition of purinoceptor agonist-induced nociception by spinorphin, but not by morphine

Cited by 38 publications

References 18 publications

Anatomical and physiological evidence for involvement of tuberoinfundibular peptide of 39 residues in nociception

Anatomical and physiological evidence for involvement of tuberoinfundibular peptide of 39 residues in nociception

Effects of A‐317491, a novel and selective P2X3/P2X2/3 receptor antagonist, on neuropathic, inflammatory and chemogenic nociception following intrathecal and intraplantar administration

Entropy-driven binding of opioid peptides induces a large domain motion in human dipeptidyl peptidase III

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Effects of A‐317491, a novel and selective P2X₃/P2X_2/3 receptor antagonist, on neuropathic, inflammatory and chemogenic nociception following intrathecal and intraplantar administration