Skip to main content

Advertisement

SpringerLink
Log in

Effects of d-kyotorphin on nociception and NADPH-d neurons in rat’s periaqueductal gray after immobilization stress

  • Original Article
  • Published:
Amino Acids Aims and scope Submit manuscript

Abstract

d-kyotorphin (d-Kyo) is a synthetic analogue of the neuropeptide kyotorphin and produces naloxone reversible analgesia. Stress-induced analgesia (SIA) is an in-built mammalian pain-suppression response that occurs during or following exposure to a stressful stimulus. The periaqueductal gray (PAG) is implicated as a critical site for processing strategies for coping with different types of stress and pain and NO affects its activity. The objectives of the present study were twofold: (1) to examine the effects of d-Kyo (5 mg/kg) on acute immobilization SIA; (2) to investigate the effect of peptide on NO activity in rat PAG after the stress procedure mentioned above. All drugs were injected intraperitoneally in male Wistar rats. The nociception was measured by the paw pressure and hot plate tests. A histochemical procedure for nicotinamide adenine dinucleotide phosphate–diaphorase (NADPH-d)-reactive neurons was used as indirect marker of NO activity. Our results revealed that d-Kyo has modulating effects on acute immobilization stress-induced analgesia in rats may be by opioid and non-opioid systems. Although d-Kyo is incapable of crossing the blood–brain barrier it showed an increased number of NADPH-d reactive neurons in dorsolateral periaqueductal gray (dlPAG) in control but not in stressed groups. We may speculate that the effect of d-Kyo in the brain is due to structural and functional interaction between opioidergic and NO-ergic systems or d-Kyo appears itself as a stressor. Further studies are needed to clarify the exact mechanisms of its action.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Aloisi AM, Ceccarelli I, Lupo C (1998) Behavioural and hormonal effects of restraint stress and formalin test in male and female rats. Brain Res Bull 47:57–62

    Article  PubMed  CAS  Google Scholar 

  • Amir S, Amit Z (1978) Endogenous opioid ligands may mediate stress-induced changes in the affective properties of pain related behavior in rats. Life Sci 23:1143–1151

    Article  PubMed  CAS  Google Scholar 

  • Amit Z, Galina ZH (1988) Stress induced analgesia plays an adaptive role in the organization of behavioral responding. Brain Res Bull 21:955–958

    Article  PubMed  CAS  Google Scholar 

  • Appelbaum BD, Holtzman SG (1985) Restraint stress enhances morphine-induced analgesia in the rat without changing apparent affinity of receptor. Life Sci 36:1069–1074

    Article  PubMed  CAS  Google Scholar 

  • Basbaum AI, Fields HL (1984) Endogenous pain control systems: brainstem spinal pathways and endorphin circuitry. Annu Rev Neurosci 7:309–338

    Article  PubMed  CAS  Google Scholar 

  • Behbehani MM (1995) Functional characteristics of the midbrain periaqueductal gray. Prog Neurobiol 46:575–605

    Article  PubMed  CAS  Google Scholar 

  • Bocheva AI, Dzambazova EB (2009) Opioidergic system and second messengers affected the nociceptive effects of Tyr-MIF-1’s after three models of stress. Bulg Chem Commun 41:153–159

    CAS  Google Scholar 

  • Bodnar RJ (1990) Effects of opioid peptides on peripheral stimulation and ‘stress’-induced analgesia in animals. Crit Rev Neurobiol 6:39–49

    PubMed  CAS  Google Scholar 

  • Bronnikov G, Dolgacheva L, Zhang SJ, Galitovskaya E, Kramarova L, Zinchenko V (1997) The effect of neuropeptides kyotorphin and neokyotorphin on proliferation of cultured brown preadipocytes. FEBS Lett 407:73–77

    Article  PubMed  CAS  Google Scholar 

  • Butler RK, Finn DP (2009) Stress-induced analgesia. Prog Neurobiol 88(3):184–202

    Article  PubMed  CAS  Google Scholar 

  • Carrasco GA, Van de Kar LD (2003) Neuroendocrine pharmacology of stress. Eur J Pharmacol 463:235–272

    Article  PubMed  CAS  Google Scholar 

  • Choi S, Lee J, Suh H (2003) Effect of ginsenosides administered intrathecally on the antinociception induced by cold water swimming stress in the mouse. Biol Pharm Bull 26:858–861

    Article  PubMed  CAS  Google Scholar 

  • Contet C, Gavériaux-Ruff C, Matifas A, Caradec C, Champy MF, Kieffer BL (2006) Dissociation of analgesic and hormonal responses to forced swim stress using opioid receptor knockout mice. Neuropsychopharmacol 31:1733–1744

    Article  CAS  Google Scholar 

  • Costa A, Trainer P, Besser M, Grossman A (1993) Nitric oxide modulates the release of corticotropin-releasing hormone from the rat hypothalamus in vitro. Brain Res 605:187–192

    Article  PubMed  CAS  Google Scholar 

  • Dzambazova EB, Bocheva AI, Nikolova VP (2009) Involvement of endogenous nitric oxide in the effects of kyotorphin and its synthetic analogue on immobilization and cold stress-induced analgesia. Bulg Chem Commun 41:116–121

    CAS  Google Scholar 

  • Fujita T, Kishida T, Okada N, Ganapathy V, Leibach FH, Yamamoto A (1999) Interaction of kyotorphin and brain peptide transporter in synaptosomes prepared from rat cerebellum: implication of high affinity type H+/peptide transporter PEPT2 mediated transport system. Neurosci Lett 271:117–120

    Article  PubMed  CAS  Google Scholar 

  • Gilinsky MA, Petrakova GM, Amstislavskaya TG, Maslova LN, Bulygina VV (2005) Hypothalamic monoamines in cold stress on the background of changes in the activity of the nitric oxide system. Neurosci Behav Physiol 35:171–175

    Article  Google Scholar 

  • Gioia M, Bianchi R (1988) The distribution of substance P and Met-enkephalin in the periaqueductal gray matter of the rat. Basic Appl Histochem 32:103–108

    PubMed  CAS  Google Scholar 

  • Hara S, Kuhns ER, Ellenberger EA, Mueller JL, Shibuya T, Endo T, Quock RM (1995) Involvement of nitric oxide in intracerebroventricular β-endorphin-induced neuronal release of methionine enkephalin. Brain Res 675:190–194

    Article  PubMed  CAS  Google Scholar 

  • Hodges BL, Gagnon MJ, Gillespie TR, Breneisen JR, O’Lealy DF, Hara S, Quock RM (1994) Antagonism of nitrous oxide antinociception in the rat hot plate test by site-specific mu and epsilon opioid receptors blockade. J Pharmacol Exp Ther 269:596–600

    PubMed  CAS  Google Scholar 

  • Hope BT, Michael GJ, Knigge KM, Vincent SR (1991) Neuronal NADPH–diaphorase is a nitric oxide synthase. Proc Natl Acad Sci USA 88:2811–2820

    Article  PubMed  CAS  Google Scholar 

  • Hori N, Lee MC, Sasaguri K, Ishii H, Kamei M, Kimoto K, Toyoda M, Sato S (2005) Suppression of stress-induced nNOS expression in the rat hypothalamus by biting. J Dent Res 84:624–628

    Article  PubMed  CAS  Google Scholar 

  • Ignarro LJ (1990) Biosynthesis and metabolism of endothelium-derived nitric oxide. Annu Rev Pharmacol 30:535–560

    Article  CAS  Google Scholar 

  • Inoue M, Yamada T, Ueda H (1999) Low dose of kyotorphin (tyrosine-arginine) induces nociceptive responses through a substance P release from nociceptor endings. Mol Brain Res 69:302–305

    Article  PubMed  CAS  Google Scholar 

  • Karanth S, Lyson K, McCann SM (1993) Role of nitric oxide in interleukin 2-induced corticotropin-releasing factor release from incubated hypothalamus. Proc Natl Acad Sci USA 90:3383–3387

    Article  PubMed  CAS  Google Scholar 

  • Lapo IB, Konarzewski M, Sadowski B (2003) Effect of cold acclimation and repeated swimming on opioid and nonopioid swim stress-induced analgesia in selectively bred mice. Physiol Behav 78:345–350

    Article  PubMed  CAS  Google Scholar 

  • Lopes SC, Fedorov A, Castanho MA (2006) Chiral recognition of d-kyotorphin by lipidic membranes: relevance toward improved analgesic efficiency. Chem Med Chem 1:723–728

    PubMed  CAS  Google Scholar 

  • Matsumoto T, Nakane M, Pollock JS, Kuk JE, Forstermann U (1993) A correlation between soluble brain nitric oxide synthase and NADPH-d activity is only seen after exposure of the tissue to fixative. Neurosci Lett 155:61–64

    Article  PubMed  CAS  Google Scholar 

  • McDonald CE, Gagnon MJ, Ellenberger EA, Hodges BL, Ream JK, Tousman SA, Quock RM (1994) Inhibitors of nitric oxide synthesis antagonize nitrous oxide antinociception in mice and rats. J Pharmacol Exp Ther 269:601–608

    PubMed  CAS  Google Scholar 

  • Ochi T, Motoyama Y, Goto T (2000) The spinal antinociceptive effect of FR140423 is mediated through kyotorphin receptors. Life Sci 66:2239–2245

    Article  PubMed  CAS  Google Scholar 

  • Onstott D, Mayer B, Beitz AJ (1993) Nitric oxide synthase immunoreac-tive neurons anatomically define a longitudinal dorsolateral column within the midbrain periaqueductal gray of the rat: analysis using laser confocal microscopy. Brain Res 610:317–324

    Article  PubMed  CAS  Google Scholar 

  • Pacák K, Palkovits M (2001) Stressor specificity of central neuroendocrine responses: implications for stress-related disorders. Endocr Rev 22:502–548

    Article  PubMed  Google Scholar 

  • Paxinos G, Watson C (1986) The rat brain in stereotaxic coordinates. Academic Press, Orlando

    Google Scholar 

  • Rodella L, Rezzani R, Agostini C, Bianchi R (1998) Induction of NADPH–diaphorase activity in the rat periaqueductal gray matter after nociceptive visceral stimulation. Brain Res 793:333–336

    Article  PubMed  CAS  Google Scholar 

  • Rodgers RJ, Randall JI (1988) Environmentally induced analgesia: situational factors, mechanisms and significance. In: Rodgers RJ, Cooper SJ (eds) Endorphins, opiates and behavioural processes. John Wiley & Sons, New York, pp 107–142

    Google Scholar 

  • Sandkühler J (1996) The organization and function of endogenous antinociceptive systems. Prog Neurobiol 50:49–81

    PubMed  Google Scholar 

  • Sargent DF, Schwyzer R (1986) Membrane lipid phase as catalyst for peptide-receptor interactions. Proc Natl Acad Sci USA 83:5774–5778

    Article  PubMed  CAS  Google Scholar 

  • Saxon DW, Beitz A (1996) Induction of NADPH–diaphorase/nitric oxide synthase in the rat brainstem trigeminal system resulting from cerebellar lesions. J Comp Neurol 371:41–71

    Article  PubMed  CAS  Google Scholar 

  • Stone TW (1983) A comparison of the effects of morphine, enkephalin, kyotorphin and d-phenylalanine on rat central neurones. Br J Pharmacol 79:305–312

    PubMed  CAS  Google Scholar 

  • Takagi H, Shiomi H, Ueda H, Amano H (1979a) A novel analgesic dipeptide from bovine brain is a possible Met-enkephalin releaser. Nature 282:410–412

    Article  PubMed  CAS  Google Scholar 

  • Takagi H, Shiomi H, Ueda H, Amano H (1979b) Morphine-like analgesia by a new dipeptide, l-tyrosyl-l-arginine (Kyotorphin) and its analogue. Eur J Pharmacol 55:109–111

    Article  PubMed  CAS  Google Scholar 

  • Takagi H, Shiomi H, Kuraishi Y, Ueda H (1982) Analgesic dipeptide, l-Tyr-d-Arg (d-kyotorphin) induces Met-enkephalin release from guinea pig striatal slices. Experientia 38:1344–1345

    Article  CAS  Google Scholar 

  • Teuscher NS, Keep RF, Smith DE (2001) PEPT2-mediated uptake of neuropeptides in rat choroid plexus. Pharm Res 18:807–813

    Article  PubMed  CAS  Google Scholar 

  • Tsuda A, Ida Y, Satoh H, Tsujimaru S, Tanaka M (1989) Stressor predictability and rat brain noradrenaline metabolism. Pharmacol Biochem Behav 32:569–572

    Article  PubMed  CAS  Google Scholar 

  • Ueda H, Yoshihara Y, Misawa H, Fukushima N, Katada T, Ui M, Takagi H, Satoh M (1989) The kyotorphin (tyrosine-arginine) receptor and a selective reconstitution with purified Gi, measured with GTPase and phospholipase C assays. J Biol Chem 264:3732–3741

    PubMed  CAS  Google Scholar 

  • Uribe RM, Lee S, Rivier C (1999) Endotoxin stimulates nitric oxide production in the paraventricular nucleus of the hypothalamus through nitric oxide synthase I: correlation with hypothalamic-pituitary-adrenal axis activation. Endocrinology 140:5971–5981

    Article  PubMed  CAS  Google Scholar 

  • Vaccarino AL, Clemmons HR, Mader GJ Jr, Magnusson JE (1997) A role of periaqueductal grey NMDA receptors in mediating formalin-induced pain in the rat. Neurosci Lett 236:117–119

    Article  PubMed  CAS  Google Scholar 

  • Watkins LR, Mayer DJ (1986) Multiple endogenous opiate and non-opiate analgesia systems: evidence of their existence and clinical implications. Ann NY Acad Sci 467:273–299

    Article  PubMed  CAS  Google Scholar 

  • Xing J, Li J (2007) TRPV1 receptor mediates glutamatergic synaptic input to dorsolateral periaqueductal gray (dl-PAG) neurons. J Neurophysiol 97:503–511

    Article  PubMed  CAS  Google Scholar 

  • Xing J, Li DP, Li J (2008) Role of GABA receptors in nitric oxide inhibition of dorsolateral periaqueductal gray neurons. Neuropharmacol 54:734–744

    Article  CAS  Google Scholar 

  • Yajima H, Ogawa H, Ueda H, Takagi H (1980) Studies on peptides. XCIV. Synthesis and activity of kyotorphin and its analogues. Chem Pharm Bull 28:1935–1938

    PubMed  CAS  Google Scholar 

  • Yamada K, Nabeshima T (1995) Stress-induced responses and multiple opioid systems in the brain. Behav Brain Res 67:133–145

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by Grant 3-D/2007 of the Medical University of Sofia, Bulgaria.

Author information

Authors and Affiliations

  1. Faculty of Medicine, Sofia University St. Kl. Ohridski, 1 Kozyak Str., 1407, Sofia, Bulgaria

    Elena B. Dzambazova

  2. Department of Pathophysiology, Medical University, 1431, Sofia, Bulgaria

    Adriana I. Bocheva

  3. Department of Anatomy and Histology, Medical University, 1431, Sofia, Bulgaria

    Boycho V. Landzhov & Anastasia A. Bozhilova-Pastirova

Authors
  1. Elena B. Dzambazova
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Boycho V. Landzhov
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Adriana I. Bocheva
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Anastasia A. Bozhilova-Pastirova
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Elena B. Dzambazova.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Dzambazova, E.B., Landzhov, B.V., Bocheva, A.I. et al. Effects of d-kyotorphin on nociception and NADPH-d neurons in rat’s periaqueductal gray after immobilization stress. Amino Acids 41, 937–944 (2011). https://doi.org/10.1007/s00726-010-0793-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00726-010-0793-y

Keywords

Search

Navigation