Advertisement

Neurochemical Research

, Volume 33, Issue 10, pp 2099–2106 | Cite as

Involvement of Spinal Somatostatin Receptor SST2A in Inflammation-Induced Thermal Hyperalgesia: Ultrastructural and Behavioral Studies in Rats

  • Jun Zhao
  • Jiang-Yuan Hu
  • Yu-Qiu Zhang
  • Zhi-Qi Zhao
Original Paper

Abstract

Our previous results have shown that somatostatin receptor subtype SST2A is responsible for thermal, but not mechanical nociceptive transmission in the rat spinal cord. The present study was undertaken to further examine the ultrastructural localization of SST2A receptor in lamina II of the spinal dorsal horn and the role of SST2A receptor in thermal hyperalgesia following Complete Freund’s Adjuvant (CFA)-induced inflammation. We found that SST2A receptors in lamina II are located primarily in postsynaptic dendrites and soma, but not in axons or synaptic terminals. CFA-induced inflammation markedly increased SST2A receptor-like immunoreactivity in lamina II. Paw withdrawal latency (PWL) evoked by noxious heating was obviously shortened 1 h after intraplantar injection of CFA, exhibiting thermal hyperalgesia. Pre-blocking SST2A activity by intrathecal pre-administration of CYN154806, a broad-spectrum antagonist of SST2 receptor, or specific antiserum against SST2A receptor (anti-SST2A) significantly attenuated thermal hyperalgesia in a dose-dependent fashion in CFA-treated rats. But, administration of anti-SST2A or CYN154806 after CFA treatment had no effect upon thermal hyperalgesia. Intrathecal application of SST2A agonist SOM-14 at different doses prior to CFA treatment did not influence thermal hyperalgesia in inflamed rats, but at a low dose shortened PWL evoked by noxious heating in normal rats. These results suggest that spinal SST2A receptors play a key role in triggering the generation, but not maintenance, of thermal hyperalgesia evoked by CFA-induced inflammation. The up-regulation of SST2A receptors in the spinal cord may be one of the mechanisms underlying inflammation-induced thermal hyperalgesia.

Keywords

Somatostatin SST2A receptor Spinal cord Thermal hyperalgesia Complete Freund’s Adjuvant Inflammation 

Abbreviations

ANOVA

Analysis of variance

anti-SST2A

Antiserum against SST2A receptor

CFA

Complete Freunds’s Adjuvant

DAB

3,3-diaminobenzidine

i.t.

Intrathecal

NGST

Normal goat serum in PBS with Triton X-100

PB

Phosphate buffer

PBS

Phosphate buffered saline

PWL

Paw withdrawal latency

SOM

Somatostatin

SOM-LI

SOM-like immunoreactive

SST

Somatostatin receptor

SST2A-LI

SST2A receptors-like immunoreactivity

Notes

Acknowledgments

We are grateful to Prof. S. Schulz for the gift of antiserum against SST2A receptor. The work was supported by grants from National Basic Research Program of China Grant (No. 2006CB500807 and 2007CB5125) for Z. Q. Zhao, Postdoctoral Science Foundation of China (1999) and Chinese Academy of Sciences KC Wong Postdoctoral Research Award Fund (2000-the 21st) for Dr. J. Y. Hu.

References

  1. 1.
    Brazeau P, Vale W, Burgus R, Ling N, Butcher M, Rivier J, Guillemin R (1973) Hypothalamic polypeptide that inhibits the secretion of immunoreactive pituitary growth hormone. Science 179:77–79PubMedCrossRefGoogle Scholar
  2. 2.
    Johansson O, Hokfelt T, Elde RP (1984) Immunohistochemical distribution of somatostatin-like immunoreactivity in the central nervous system of the adult rat. Neuroscience 13:265–339PubMedCrossRefGoogle Scholar
  3. 3.
    Esclapez M, Houser CR (1995) Somatostatin neurons are a subpopulation of GABA neurons in the rat dentate gyrus: evidence from colocalization of pre-prosomatostatin and glutamate decarboxylase messenger RNAs. Neuroscience 64:339–355PubMedCrossRefGoogle Scholar
  4. 4.
    Epelbaum J, Dournaud P, Fodor M, Viollet C (1994) The neurobiology of somatostatin. Crit Rev Neurobiol 8:25–44PubMedGoogle Scholar
  5. 5.
    Yamada Y, Post SR, Wang K, Tager HS, Bell GI, Seino S (1992) Cloning and functional characterization of a family of human and mouse somatostatin receptors expressed in brain, gastrointestinal tract, and kidney. Proc Natl Acad Sci USA 89:251–255PubMedCrossRefGoogle Scholar
  6. 6.
    Vanetti M, Kouba M, Wang X, Vogt G, Hollt V (1992) Cloning and expression of a novel mouse somatostatin receptor (SSTR2B). FEBS Lett 311:290–294PubMedCrossRefGoogle Scholar
  7. 7.
    Vanetti M, Vogt G, Hollt V (1993) The two isoforms of the mouse somatostatin receptor (mSSTR2A and mSSTR2B) differ in coupling efficiency to adenylate cyclase and in agonist-induced receptor desensitization. FEBS Lett 331:260–266PubMedCrossRefGoogle Scholar
  8. 8.
    Hokfelt T, Elde R, Johansson O, Luft R, Arimura A (1975) Immunohistochemical evidence for the presence of somatostatin, a powerful inhibitory peptide, in some primary sensory neurons. Neurosci Lett 1:231–235CrossRefGoogle Scholar
  9. 9.
    Hokfelt T, Elde R, Johansson O, Luft R, Nilsson G, Arimura A (1976) Immunohistochemical evidence for separate populations of somatostatin-containing and substance P-containing primary afferent neurons in the rat. Neuroscience 1:131–136PubMedCrossRefGoogle Scholar
  10. 10.
    Nagy JI, Hunt SP, Iversen LL, Emson PC (1981) Biochemical and anatomical observations on the degeneration of peptide-containing primary afferent neurons after neonatal capsaicin. Neuroscience 6:1923–1934PubMedCrossRefGoogle Scholar
  11. 11.
    Kummer W, Heym C (1986) Correlation of neuronal size and peptide immunoreactivity in the guinea-pig trigeminal ganglion. Cell Tissue Res 245:657–665PubMedCrossRefGoogle Scholar
  12. 12.
    Tuchscherer MM, Seybold VS (1989) A quantitative study of the coexistence of peptides in varicosities within the superficial laminae of the dorsal horn of the rat spinal cord. J Neurosci 9:195–205PubMedGoogle Scholar
  13. 13.
    Garry MG, Miller KE, Seybold VS (1989) Lumbar dorsal root ganglia of the cat: a quantitative study of peptide immunoreactivity and cell size. J Comp Neurol 284:36–47PubMedCrossRefGoogle Scholar
  14. 14.
    Hanesch U, Heppelmann B, Schmidt RF (1995) Somatostatin-like immunoreactivity in primary afferents of the medial articular nerve and colocalization with substance P in the cat. J Comp Neurol 354:345–352PubMedCrossRefGoogle Scholar
  15. 15.
    Li CQ, Zhao ZQ, Yang HQ (1991) Effects of cysteamine on flexion reflex facilitation by C-primary afferents in cats. Zhongguo Yao Li Xue Bao 12:199–202PubMedGoogle Scholar
  16. 16.
    Tuchscherer MM, Seybold VS (1985) Immunohistochemical studies of substance P, cholecystokinin-octapeptide and somatostatin in dorsal root ganglia of the rat. Neuroscience 14:593–605PubMedCrossRefGoogle Scholar
  17. 17.
    Wiesenfeld-Hallin Z (1985) Intrathecal somatostatin modulates spinal sensory and reflex mechanisms: behavioral and electrophysiological studies in the rat. Neurosci Lett 62:69–74PubMedCrossRefGoogle Scholar
  18. 18.
    Wiesenfeld-Hallin Z (1986) Substance P and somatostatin modulate spinal cord excitability via physiologically different sensory pathways. Brain Res 372:172–175PubMedCrossRefGoogle Scholar
  19. 19.
    Ohno H, Kuraishi Y, Minami M, Satoh M (1988) Modality-specific antinociception produced by intrathecal injection of anti-somatostatin antiserum in rats. Brain Res 474:197–200PubMedCrossRefGoogle Scholar
  20. 20.
    Traub RJ, Brozoski D (1996) Anti-somatostatin antisera, but neither a somatostatin agonist (octreotide) nor antagonist (CYCAM), attenuates hyperalgesia in the rat. Peptides 17:769–773PubMedCrossRefGoogle Scholar
  21. 21.
    Mollenholt P, Post C, Rawal N, Freedman J, Hokfelt T, Paulsson I (1988) Antinociceptive and ‘neurotoxic’ actions of somatostatin in rat spinal cord after intrathecal administration. Pain 32:95–105PubMedCrossRefGoogle Scholar
  22. 22.
    Mollenholt P, Post C, Paulsson I, Rawal N (1990) Intrathecal and epidural somatostatin in rats: can antinociception, motor effects and neurotoxicity be separated? Pain 43:363–370PubMedCrossRefGoogle Scholar
  23. 23.
    Sandkuhler J, Fu QG, Helmchen C (1990) Spinal somatostatin superfusion in vivo affects activity of cat nociceptive dorsal horn neurons: comparison with spinal morphine. Neuroscience 34:565–576PubMedCrossRefGoogle Scholar
  24. 24.
    Fodor M, Slama A, Guillaume V, Videau C, Csaba Z, Oliver C, Epelbaum J (1997) Distribution and pharmacological characterization of somatostatin receptor binding sites in the sheep brain. J Chem Neuroanat 12:175–182PubMedCrossRefGoogle Scholar
  25. 25.
    Uhl GR, Tran V, Snyder SH, Martin JB (1985) Somatostatin receptors: distribution in rat central nervous system and human frontal cortex. J Comp Neurol 240:288–304PubMedCrossRefGoogle Scholar
  26. 26.
    Ohno H, Kuraishi Y, Nanayama T, Minami M, Kawamura M, Satoh M (1990) Somatostatin is increased in the dorsal root ganglia of adjuvant-inflamed rat. Neurosci Res 8:179–188PubMedCrossRefGoogle Scholar
  27. 27.
    Schulz S, Schmidt H, Handel M, Schreff M, Hollt V (1998) Differential distribution of alternatively spliced somatostatin receptor 2 isoforms (sst2A and sst2B) in rat spinal cord. Neurosci Lett 257:37–40PubMedCrossRefGoogle Scholar
  28. 28.
    Schulz S, Schreff M, Schmidt H, Handel M, Przewlocki R, Hollt V (1998) Immunocytochemical localization of somatostatin receptor sst2A in the rat spinal cord and dorsal root ganglia. Eur J Neurosci 10:3700–3708PubMedCrossRefGoogle Scholar
  29. 29.
    Song P, Hu JY, Zhao ZQ (2002) Spinal somatostatin SSTR2A receptors are preferentially up-regulated and involved in thermonociception but not mechanonociception. Exp Neurol 178:280–287PubMedCrossRefGoogle Scholar
  30. 30.
    Zimmermann M (1983) Ethical guidelines for investigations of experimental pain in conscious animals. Pain 16:109–110PubMedCrossRefGoogle Scholar
  31. 31.
    Hsu SM, Raine L, Fanger H (1981) Use of avidin–biotin–peroxidase complex (ABC) in immunoperoxidase techniques: a comparison between ABC and unlabeled antibody (PAP) procedures. J Histochem Cytochem 29:577–580PubMedGoogle Scholar
  32. 32.
    Jensen TS, Smith DF (1982) Role of 5-HT and NA in spinal dopaminergic analgesia. Eur J Pharmacol 86:65–70PubMedCrossRefGoogle Scholar
  33. 33.
    Kuraishi Y, Hirota N, Sato Y, Hino Y, Satoh M, Takagi H (1985) Evidence that substance P and somatostatin transmit separate information related to pain in the spinal dorsal horn. Brain Res 325:294–298PubMedCrossRefGoogle Scholar
  34. 34.
    Morton CR, Hutchison WD, Hendry IA, Duggan AW (1989) Somatostatin: evidence for a role in thermal nociception. Brain Res 488:89–96PubMedCrossRefGoogle Scholar
  35. 35.
    Liu H, Yang HQ, Zhao ZQ (1998) The functional differentiation of substance P and somatostatin in mediating spinal nociception. Chin J Neurosci 14:146–150Google Scholar
  36. 36.
    Yang HQ, Zhao ZQ, Liu Y (1994) Preferential inhibition of responses of spinal dorsal horn neurons to noxious heat by cysteamine in the cat. Chin J Physiol Sci 10:79–84Google Scholar
  37. 37.
    Handel M, Schulz S, Stanarius A, Schreff M, Erdtmann-Vourliotis M, Schmidt H, Wolf G, Hollt V (1999) Selective targeting of somatostatin receptor 3 to neuronal cilia. Neuroscience 89:909–926PubMedCrossRefGoogle Scholar
  38. 38.
    Gao YJ, Zhang YQ, Zhao ZQ (2003) Involvement of spinal neurokinin-1 receptors in the maintenance but not induction of carrageenan-induced thermal hyperalgesia in the rat. Brain Res Bull 61:587–593PubMedCrossRefGoogle Scholar
  39. 39.
    De Felipe C, Herrero JF, O’Brien JA, Palmer JA, Doyle CA, Smith AJ, Laird JM, Belmonte C, Cervero F, Hunt SP (1998) Altered nociception, analgesia and aggression in mice lacking the receptor for substance P. Nature 392:394–397PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Jun Zhao
    • 1
    • 2
  • Jiang-Yuan Hu
    • 1
    • 2
    • 3
  • Yu-Qiu Zhang
    • 1
    • 2
  • Zhi-Qi Zhao
    • 1
    • 2
    • 4
  1. 1.Institute of NeurobiologyInstitutes of Brain Science, Fu-Dan UniversityShanghaiPeople’s Republic of China
  2. 2.State Key Laboratory of Medical NeurobiologyFu-Dan UniversityShanghaiPeople’s Republic of China
  3. 3.Center for Neurobiology and BehaviorColumbia University College of Physicians and SurgeonsNew YorkUSA
  4. 4.Institute of NeurobiologyFu-Dan UniversityShanghaiPeople’s Republic of China

Personalised recommendations