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Brain opioid and nociceptin receptors are involved in regulation of bombesin-induced activation of central sympatho-adrenomedullary outflow in the rat

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Abstract

Previously, we reported that central administration of bombesin, a stress-related peptide, elevated plasma levels of catecholamines (noradrenaline and adrenaline) in the rat. The sympatho-adrenomedullary system, which is an important component of stress responses, can be regulated by the central opioid system. In the present study, therefore, we examined the roles of brain opioid receptor subtypes (µ, δ, and κ) and nociceptin receptors, originally identified as opioid-like orphan receptors, in the bombesin-induced activation of central sympatho-adrenomedullary outflow using anesthetized male Wistar rats. Intracerebroventricularly (i.c.v.) administered bombesin-(1 nmol/animal) induced elevation of plasma catecholamines was significantly potentiated by pretreatment with naloxone (300 and 1000 µg/animal, i.c.v.), a non-selective antagonist for µ-, δ-, and κ-opioid receptors. Pretreatment with cyprodime (100 µg/animal, i.c.v.), a selective antagonist for µ-opioid receptors, also potentiated the bombesin-induced responses. In contrast, pretreatment with naltrindole (100 µg/animal, i.c.v.) or nor-binaltorphimine (100 µg/animal, i.c.v.), a selective antagonist for δ- or κ-opioid receptors, significantly reduced the elevation of bombesin-induced catecholamines. In addition, pretreatment with JTC-801 (30 and 100 µg/animal, i.c.v.) or J-113397 (100 µg/animal, i.c.v.), which are selective antagonists for nociceptin receptors, also reduced the bombesin-induced responses. These results suggest that brain µ-opioid receptors play a suppressive role and that brain δ-, κ-opioid, and nociceptin receptors play a facilitative role in the bombesin-induced elevation of plasma catecholamines in the rat. Thus, in the brain, these receptors could play differential roles in regulating the activation of central sympatho-adrenomedullary outflow.

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Abbreviations

ANOVA:

Analysis of variance

AUC:

Area under the curve

DMF:

N,N-dimethylformamide

GRP:

Gastrin-releasing peptide

HPLC:

High performance liquid chromatography

i.c.v.:

Intracerebroventricularly

NMB:

Neuromedin B

References

  1. Bartolomucci A, Palanza P, Costoli T, Savani E, Laviola G, Parmigiani S, Sgoifo A (2003) Chronic psychosocial stress persistently alters autonomic function and physical activity in mice. Physiol Behav 80:57–67

    Article  CAS  PubMed  Google Scholar 

  2. Ulrich-Lai YM, Herman JP (2009) Neural regulation of endocrine and autonomic stress responses. Nat Rev Neurosci 10:397–409

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. Fontes MA, Xavier CH, Marins FR, Limborço-Filho M, Vaz GC, Müller-Ribeiro FC, Nalivaiko E (2014) Emotional stress and sympathetic activity: contribution of dorsomedial hypothalamus to cardiac arrhythmias. Brain Res 1554:49–58

    Article  CAS  PubMed  Google Scholar 

  4. Tank AW, Lee Wong D (2015) Peripheral and central effects of circulating catecholamines. Compr Physiol 5:1–15

    PubMed  Google Scholar 

  5. Vanitallie TB (2002) Stress: a risk factor for serious illness. Metabolism 51:40–45

    Article  CAS  PubMed  Google Scholar 

  6. Esler M (2009) Heart and mind: psychogenic cardiovascular disease. J Hypertens 27:692–695

    Article  CAS  PubMed  Google Scholar 

  7. Grassi G, Seravalle G, Quarti-Trevano F (2010) The ‘neuroadrenergic hypothesis’ in hypertension: current evidence. Exp Physiol 95:581–586

    Article  PubMed  Google Scholar 

  8. Holden JE, Jeong Y, Forrest JM (2005) The endogenous opioid system and clinical pain management. AACN Clin 16:291–301

    Article  Google Scholar 

  9. Drolet G, Dumont EC, Gosselin I, Kinkead R, Laforest S, Trottier JF (2001) Role of endogenous opioid system in the regulation of the stress response. Prog Neuropsychopharmacol Biol Psychiatry 25:729–741

    Article  CAS  PubMed  Google Scholar 

  10. Bilkei-Gorzo A, Racz I, Michel K, Mauer D, Zimmer A, Klingmüller D, Zimmer A (2008) Control of hormonal stress reactivity by the endogenous opioid system. Psychoneuroendocrinology 33:425–436

    Article  CAS  PubMed  Google Scholar 

  11. Bodnar RJ (2011) Endogenous opiates and behavior: 2010. Peptides 32:2522–2552

    Article  CAS  PubMed  Google Scholar 

  12. Dhawan BN, Cesselin F, Raghubir R, Reisine T, Bradley PB, Portoghese PS, Hamon M (1996) International union of pharmacology. XII. Classification of opioid receptors. Pharmacol Rev 48:567–592

    CAS  PubMed  Google Scholar 

  13. Zöllner C, Stein C (2007) Opioids. Handb Exp Pharmacol 177:31–63

    Article  PubMed  Google Scholar 

  14. Mogil JS, Pasternak GW (2001) The molecular and behavioral pharmacology of the orphanin FQ/nociceptin peptide and receptor family. Pharmacol Rev 53:381–415

    CAS  PubMed  Google Scholar 

  15. Le Merrer J, Becker JA, Befort K, Kieffer BL (2009) Reward processing by the opioid system in the brain. Physiol Rev 89:1379–1412

    Article  PubMed Central  PubMed  Google Scholar 

  16. McCubbin JA (1993) Stress and endogenous opioids: behavioral and circulatory interactions. Biol Psychol 35:91–122

    Article  CAS  PubMed  Google Scholar 

  17. Janssens CJ, Helmond FA, Loyens LW, Schouten WG, Wiegant VM (1995) Chronic stress increases the opioid-mediated inhibition of the pituitary-adrenocortical response to acute stress in pigs. Endocrinology 136:1468–1473

    CAS  PubMed  Google Scholar 

  18. Kawabe T, Kawabe K, Sapru HN (2012) Cardiovascular responses to chemical stimulation of the hypothalamic arcuate nucleus in the rat: role of the hypothalamic paraventricular nucleus. PLoS One 7:e45180

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Krowicki ZK, Kapusta DR (2006) Tonic nociceptinergic inputs to neurons in the hypothalamic paraventricular nucleus contribute to sympathetic vasomotor tone and water and electrolyte homeostasis in conscious rats. J Pharmacol Exp Ther 317:446–453

    Article  CAS  PubMed  Google Scholar 

  20. May CN, Whitehead CJ, Mathias CJ (1991) The pressor response to central administration of beta-endorphin results from a centrally mediated increase in noradrenaline release and adrenaline secretion. Br J Pharmacol 102:639–644

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Arndt ML, Wu D, Soong Y, Szeto HH (1999) Nociceptin/orphanin FQ increases blood pressure and heart rate via sympathetic activation in sheep. Peptides 20:465–470

    Article  CAS  PubMed  Google Scholar 

  22. Anastasi A, Erspamer V, Bucci M (1971) Isolation and structure of bombesin and alytesin, 2 analogous active peptides from the skin of the European amphibians Bombina and Alytes. Experientia 27:166–167

    Article  CAS  PubMed  Google Scholar 

  23. Jensen RT, Battery JF, Spindel ER, Benya RV (2008) International union of pharmacology. LXVIII. Mammalian bombesin receptors: nomenclature, distribution, pharmacology, signaling and functions in normal and disease states. Pharmacol Rev 60:1–42

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Merali Z, Kent P, Anisman H (2002) Role of bombesin-related peptides in the mediation or integration of the stress response. Cell Mol Life Sci 59:272–287

    Article  CAS  PubMed  Google Scholar 

  25. Yokotani K, Okada S, Nakamura K, Yamaguchi-Shima N, Shimizu T, Arai J, Wakiguchi H, Yokotani K (2005) Brain prostanoid TP receptor-mediated adrenal noradrenaline secretion and EP3 receptor-mediated sympathetic noradrenaline release in rats. Eur J Pharmacol 512:29–35

    Article  CAS  PubMed  Google Scholar 

  26. Tanaka K, Shimizu T, Yanagita T, Nemoto T, Nakamura K, Taniuchi K, Dimitriadis F, Yokotani K, Saito M (2014) Brain RVD-haemopressin, a haemoglobin-derived peptide, inhibits bombesin-induced central activation of adrenomedullary outflow in the rat. Br J Pharmacol 171:202–213

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. Shimizu T, Okada S, Yamaguchi-Shima N, Yokotani K (2004) Brain phospholipase C-diacylglycerol lipase pathway is involved in vasopressin-induced release of noradrenaline and adrenaline from adrenal medulla in rats. Eur J Pharmacol 499:99–105

    Article  CAS  PubMed  Google Scholar 

  28. Paxinos G, Watson C (2005) In: Paxinos G, Watson C (eds) The rat brain in stereotaxic coordinates. Elsevier Academic Press, Burlington

    Google Scholar 

  29. Anton AH, Sayre DF (1962) A study of the factors affecting the aluminum oxide-trihydroxyindole procedure for the analysis of catecholamines. J Pharmacol Exp Ther 138:360–375

    CAS  PubMed  Google Scholar 

  30. Martinez A, Padbury J, Shames L, Evans C, Humme J (1988) Naloxone potentiates epinephrine release during hypoxia in fetal sheep: dose response and cardiovascular effects. Pediatr Res 23:343–347

    Article  CAS  PubMed  Google Scholar 

  31. Appel NM, Kiritsy-Roy JA, van Loon GR (1986) Mu receptors at discrete hypothalamic and brainstem sites mediate opioid peptide-induced increases in central sympathetic outflow. Brain Res 378:8–20

    Article  CAS  PubMed  Google Scholar 

  32. May CN, Dashwood MR, Whitehead CJ, Mathias CJ (1989) Differential cardiovascular and respiratory responses to central administration of selective opioid agonists in conscious rabbits: correlation with receptor distribution. Br J Pharmacol 98:903–913

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Sun SY, Liu Z, Li P, Ingenito AJ (1996) Central effects of opioid agonists and naloxone on blood pressure and heart rate in normotensive and hypertensive rats. Gen Pharmacol 27:1187–1194

    Article  CAS  PubMed  Google Scholar 

  34. Kiritsy-Roy JA, Appel NM, Bobbitt FG, Van Loon GR (1986) Effects of mu-opioid receptor stimulation in the hypothalamic paraventricular nucleus on basal and stress-induced catecholamine secretion and cardiovascular responses. J Pharmacol Exp Ther 239:814–822

    CAS  PubMed  Google Scholar 

  35. Márki A, Monory K, Otvös F, Tóth G, Krassnig R, Schmidhammer H, Traynor JR, Roques BP, Maldonado R, Borsodi A (1999) Mu-opioid receptor specific antagonist cyprodime: characterization by in vitro radioligand and [35S]GTPγS binding assays. Eur J Pharmacol 383:209–214

    Article  PubMed  Google Scholar 

  36. Valentino RJ, Van Bockstaele E (2015) Endogenous opioids: the downside of opposing stress. Neurobiol Stress 1:23–32

    Article  PubMed Central  PubMed  Google Scholar 

  37. Kraft K, Diehl J, Stumpe KO (1991) Influence of chronic opioid delta receptor antagonism on blood pressure development and tissue contents of catecholamines and endogenous opioids in spontaneously hypertensive rats. Clin Exp Hypertens A 13:467–477

    CAS  PubMed  Google Scholar 

  38. Emmerson PJ, Liu MR, Woods JH, Medzihradsky F (1994) Binding affinity and selectivity of opioids at mu, delta and kappa receptors in monkey brain membranes. J Pharmacol Exp Ther 271:1630–1637

    CAS  PubMed  Google Scholar 

  39. Shen S, Ingenito AJ (1999) Comparison of cardiovascular responses to intra-hippocampal mu, delta and kappa opioid agonists in spontaneously hypertensive rats and isolation-induced hypertensive rats. J Hypertens 17:497–505

    Article  CAS  PubMed  Google Scholar 

  40. Shen S, Ingenito AJ (2000) Chronic blockade of hippocampal kappa receptors increases arterial pressure in conscious spontaneously hypertensive rats but not in normotensive Wistar Kyoto rats. Clin Exp Hypertens 22:507–519

    Article  CAS  PubMed  Google Scholar 

  41. Pan ZZ (1998) Mu-opposing actions of the kappa-opioid receptor. Trends Pharmacol Sci 19:94–98

    Article  CAS  PubMed  Google Scholar 

  42. Bunzow JR, Saez C, Mortrud M, Bouvier C, Williams JT, Low M, Grandy DK (1994) Molecular cloning and tissue distribution of a putative member of the rat opioid receptor gene family that is not a mu, delta or kappa opioid receptor type. FEBS Lett 347:284–288

    Article  CAS  PubMed  Google Scholar 

  43. Calo’ G, Bigoni R, Rizzi A, Guerrini R, Salvadori S, Regoli D (2000) Nociceptin/orphanin FQ receptor ligands. Peptides 21:935–947

    Article  PubMed  Google Scholar 

  44. Kapusta DR, Chang JK, Kenigs VA (1999) Central administration of [Phe1Ψ(CH2-NH)Gly2]nociceptin(1-13)-NH2 and orphanin FQ/nociceptin (OFQ/N) produce similar cardiovascular and renal responses in conscious rats. J Pharmacol Exp Ther 289:173–180

    CAS  PubMed  Google Scholar 

  45. Mao L, Wang JQ (2000) Microinjection of nociceptin (Orphanin FQ) into nucleus tractus solitarii elevates blood pressure and heart rate in both anesthetized and conscious rats. J Pharmacol Exp Ther 294:255–262

    CAS  PubMed  Google Scholar 

  46. Yamada H, Nakamoto H, Suzuki Y, Ito T, Aisaka K (2002) Pharmacological profiles of a novel opioid receptor-like1 (ORL1) receptor antagonist, JTC-801. Br J Pharmacol 135:323–332

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  47. Lambert DG (2008) The nociceptin/orphanin FQ receptor: a target with broad therapeutic potential. Nat Rev Drug Discov 7:694–710

    Article  CAS  PubMed  Google Scholar 

  48. Ozaki S, Kawamoto H, Itoh Y, Miyaji M, Azuma T, Ichikawa D, Nambu H, Iguchi T, Iwasawa Y, Ohta H (2000) In vitro and in vivo pharmacological characterization of J-113397, a potent and selective non-peptidyl ORL1 receptor antagonist. Eur J Pharmacol 402:45–53

    Article  CAS  PubMed  Google Scholar 

  49. Tekes K, Hantos M, Bizderi B, Gyenge M, Kecskeméti V, Huszti Z (2005) Stimulating effect of nociceptin on histamine release in the rat brain? Inflamm Res 54(Suppl 1):S38–S39

    Article  CAS  PubMed  Google Scholar 

  50. Shimizu T, Okada S, Yamaguchi N, Sasaki T, Lu L, Yokotani K (2006) Centrally administered histamine evokes the adrenal secretion of noradrenaline and adrenaline by brain cyclooxygenase-1- and thromboxane A2-mediated mechanisms in rats. Eur J Pharmacol 541:152–157

    Article  CAS  PubMed  Google Scholar 

  51. Okuma Y, Yokotani K, Murakami Y, Osumi Y (1997) Brain histamine mediates the bombesin-induced central activation of sympatho-adrenomedullary outflow. Life Sci 61:2521–2528

    Article  CAS  PubMed  Google Scholar 

  52. Kent P, Anisman H, Merali Z (1998) Are bombesin-like peptides involved in the mediation of stress response? Life Sci 62:103–114

    Article  CAS  PubMed  Google Scholar 

  53. Merali Z, McIntosh J, Kent P, Michaud D, Anisman H (1998) Aversive and appetitive events evoke the release of corticotropin-releasing hormone and bombesin-like peptides at the central nucleus of the amygdala. J Neurosci 18:4758–4766

    CAS  PubMed  Google Scholar 

  54. Merali Z, Anisman H, James JS, Kent P, Schulkin J (2008) Effects of corticosterone on corticotrophin-releasing hormone and gastrin-releasing peptide release in response to an aversive stimulus in two regions of the forebrain (central nucleus of the amygdala and prefrontal cortex). Eur J Neurosci 28:165–172

    Article  PubMed  Google Scholar 

  55. Bédard T, Mountney C, Kent P, Anisman H, Merali Z (2007) Role of gastrin-releasing peptide and neuromedin B in anxiety and fear-related behavior. Behav Brain Res 179:133–140

    Article  PubMed  Google Scholar 

  56. Merali Z, Bédard T, Andrews N, Davis B, McKnight AT, Gonzalez MI, Pritchard M, Kent P, Anisman H (2006) Bombesin receptors as a novel anti-anxiety therapeutic target: BB1 receptor actions on anxiety through alterations of serotonin activity. J Neurosci 26:10387–10396

    Article  CAS  PubMed  Google Scholar 

  57. Shimizu T, Okada S, Yamaguchi N, Arai J, Wakiguchi H, Yokotani K (2005) Brain phospholipase C/diacylglycerol lipase are involved in bombesin BB2 receptor-mediated activation of sympatho-adrenomedullary outflow in rats. Eur J Pharmacol 514:151–158

    Article  CAS  PubMed  Google Scholar 

  58. Andoh T, Kuwazono T, Lee JB, Kuraishi Y (2011) Gastrin-releasing peptide induces itch-related responses through mast cell degranulation in mice. Peptides 32:2098–2103

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported in part by a Grant-in-Aid for Scientific Research (C) (No. 26460909 to T.S.) and a Grant-in-Aid for Young Scientists (B) (No. 23790744 to T.S.) from the Japan Society for the Promotion of Science, a grant from The Smoking Research Foundation in Japan, a grant from The Japan Health Foundation, and a Discretionary Grant of the President of Kochi University.

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Correspondence to Takahiro Shimizu.

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Toshio Yawata and Youichirou Higashi have contributed equally to this work.

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Yawata, T., Higashi, Y., Shimizu, T. et al. Brain opioid and nociceptin receptors are involved in regulation of bombesin-induced activation of central sympatho-adrenomedullary outflow in the rat. Mol Cell Biochem 411, 201–211 (2016). https://doi.org/10.1007/s11010-015-2582-0

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