Molecular and Cellular Biochemistry

, Volume 411, Issue 1–2, pp 201–211 | Cite as

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

  • Toshio Yawata
  • Youichirou Higashi
  • Takahiro Shimizu
  • Shogo Shimizu
  • Kumiko Nakamura
  • Keisuke Taniuchi
  • Tetsuya Ueba
  • Motoaki Saito


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.


Opioid receptor Nociceptin receptor Bombesin Brain Sympatho-adrenomedullary system 



Analysis of variance


Area under the curve




Gastrin-releasing peptide


High performance liquid chromatography




Neuromedin B



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.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.


  1. 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 80:57–67CrossRefPubMedGoogle Scholar
  2. 2.
    Ulrich-Lai YM, Herman JP (2009) Neural regulation of endocrine and autonomic stress responses. Nat Rev Neurosci 10:397–409PubMedCentralCrossRefPubMedGoogle Scholar
  3. 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 1554:49–58CrossRefPubMedGoogle Scholar
  4. 4.
    Tank AW, Lee Wong D (2015) Peripheral and central effects of circulating catecholamines. Compr Physiol 5:1–15PubMedGoogle Scholar
  5. 5.
    Vanitallie TB (2002) Stress: a risk factor for serious illness. Metabolism 51:40–45CrossRefPubMedGoogle Scholar
  6. 6.
    Esler M (2009) Heart and mind: psychogenic cardiovascular disease. J Hypertens 27:692–695CrossRefPubMedGoogle Scholar
  7. 7.
    Grassi G, Seravalle G, Quarti-Trevano F (2010) The ‘neuroadrenergic hypothesis’ in hypertension: current evidence. Exp Physiol 95:581–586CrossRefPubMedGoogle Scholar
  8. 8.
    Holden JE, Jeong Y, Forrest JM (2005) The endogenous opioid system and clinical pain management. AACN Clin 16:291–301CrossRefGoogle Scholar
  9. 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 25:729–741CrossRefPubMedGoogle Scholar
  10. 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 33:425–436CrossRefPubMedGoogle Scholar
  11. 11.
    Bodnar RJ (2011) Endogenous opiates and behavior: 2010. Peptides 32:2522–2552CrossRefPubMedGoogle Scholar
  12. 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 48:567–592PubMedGoogle Scholar
  13. 13.
    Zöllner C, Stein C (2007) Opioids. Handb Exp Pharmacol 177:31–63CrossRefPubMedGoogle Scholar
  14. 14.
    Mogil JS, Pasternak GW (2001) The molecular and behavioral pharmacology of the orphanin FQ/nociceptin peptide and receptor family. Pharmacol Rev 53:381–415PubMedGoogle Scholar
  15. 15.
    Le Merrer J, Becker JA, Befort K, Kieffer BL (2009) Reward processing by the opioid system in the brain. Physiol Rev 89:1379–1412PubMedCentralCrossRefPubMedGoogle Scholar
  16. 16.
    McCubbin JA (1993) Stress and endogenous opioids: behavioral and circulatory interactions. Biol Psychol 35:91–122CrossRefPubMedGoogle Scholar
  17. 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 136:1468–1473PubMedGoogle Scholar
  18. 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:e45180PubMedCentralCrossRefPubMedGoogle Scholar
  19. 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 317:446–453CrossRefPubMedGoogle Scholar
  20. 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 102:639–644PubMedCentralCrossRefPubMedGoogle Scholar
  21. 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 20:465–470CrossRefPubMedGoogle Scholar
  22. 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 27:166–167CrossRefPubMedGoogle Scholar
  23. 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 60:1–42PubMedCentralCrossRefPubMedGoogle Scholar
  24. 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 59:272–287CrossRefPubMedGoogle Scholar
  25. 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 512:29–35CrossRefPubMedGoogle Scholar
  26. 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 171:202–213PubMedCentralCrossRefPubMedGoogle Scholar
  27. 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 499:99–105CrossRefPubMedGoogle Scholar
  28. 28.
    Paxinos G, Watson C (2005) In: Paxinos G, Watson C (eds) The rat brain in stereotaxic coordinates. Elsevier Academic Press, BurlingtonGoogle Scholar
  29. 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 138:360–375PubMedGoogle Scholar
  30. 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 23:343–347CrossRefPubMedGoogle Scholar
  31. 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 378:8–20CrossRefPubMedGoogle Scholar
  32. 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 98:903–913PubMedCentralCrossRefPubMedGoogle Scholar
  33. 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 27:1187–1194CrossRefPubMedGoogle Scholar
  34. 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 239:814–822PubMedGoogle Scholar
  35. 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 383:209–214CrossRefPubMedGoogle Scholar
  36. 36.
    Valentino RJ, Van Bockstaele E (2015) Endogenous opioids: the downside of opposing stress. Neurobiol Stress 1:23–32PubMedCentralCrossRefPubMedGoogle Scholar
  37. 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 13:467–477PubMedGoogle Scholar
  38. 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 271:1630–1637PubMedGoogle Scholar
  39. 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 17:497–505CrossRefPubMedGoogle Scholar
  40. 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 22:507–519CrossRefPubMedGoogle Scholar
  41. 41.
    Pan ZZ (1998) Mu-opposing actions of the kappa-opioid receptor. Trends Pharmacol Sci 19:94–98CrossRefPubMedGoogle Scholar
  42. 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 347:284–288CrossRefPubMedGoogle Scholar
  43. 43.
    Calo’ G, Bigoni R, Rizzi A, Guerrini R, Salvadori S, Regoli D (2000) Nociceptin/orphanin FQ receptor ligands. Peptides 21:935–947CrossRefPubMedGoogle Scholar
  44. 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 289:173–180PubMedGoogle Scholar
  45. 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 294:255–262PubMedGoogle Scholar
  46. 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 135:323–332PubMedCentralCrossRefPubMedGoogle Scholar
  47. 47.
    Lambert DG (2008) The nociceptin/orphanin FQ receptor: a target with broad therapeutic potential. Nat Rev Drug Discov 7:694–710CrossRefPubMedGoogle Scholar
  48. 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 402:45–53CrossRefPubMedGoogle Scholar
  49. 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–S39CrossRefPubMedGoogle Scholar
  50. 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 541:152–157CrossRefPubMedGoogle Scholar
  51. 51.
    Okuma Y, Yokotani K, Murakami Y, Osumi Y (1997) Brain histamine mediates the bombesin-induced central activation of sympatho-adrenomedullary outflow. Life Sci 61:2521–2528CrossRefPubMedGoogle Scholar
  52. 52.
    Kent P, Anisman H, Merali Z (1998) Are bombesin-like peptides involved in the mediation of stress response? Life Sci 62:103–114CrossRefPubMedGoogle Scholar
  53. 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 18:4758–4766PubMedGoogle Scholar
  54. 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 28:165–172CrossRefPubMedGoogle Scholar
  55. 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 179:133–140CrossRefPubMedGoogle Scholar
  56. 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 26:10387–10396CrossRefPubMedGoogle Scholar
  57. 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 514:151–158CrossRefPubMedGoogle Scholar
  58. 58.
    Andoh T, Kuwazono T, Lee JB, Kuraishi Y (2011) Gastrin-releasing peptide induces itch-related responses through mast cell degranulation in mice. Peptides 32:2098–2103CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Toshio Yawata
    • 1
  • Youichirou Higashi
    • 2
  • Takahiro Shimizu
    • 2
  • Shogo Shimizu
    • 2
  • Kumiko Nakamura
    • 2
  • Keisuke Taniuchi
    • 3
  • Tetsuya Ueba
    • 1
  • Motoaki Saito
    • 2
  1. 1.Department of Neurosurgery, Kochi Medical SchoolKochi UniversityNankokuJapan
  2. 2.Department of Pharmacology, Kochi Medical SchoolKochi UniversityNankokuJapan
  3. 3.Department of Gastroenterology and Hepatology, Kochi Medical SchoolKochi UniversityNankokuJapan

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