Skip to main content
SpringerLink
Log in

The effects of phorbol ester on slowly conducting afferents of the cat's knee joint

  • Published:
Experimental Brain Research Aims and scope Submit manuscript

Summary

The effects of β -phorbol 12, 13-dibutyrate (PDBu) on the discharge properties of slowly conducting knee joint afferents (group III and group IV fibers) were studied to determine the role of protein kinase C in nociception. Extracellular single unit recordings were made from small filaments dissected from the medial articular nerve in cats anesthetized with alphachloralose. PDBu was applied intra-arterially close to the joint in concentrations of 10-6 up to 10-4 M. The afferents were classified as low-threshold and high-threshold units with regard to their sensitivity to passive noxious and innocuous movements of the knee joint. Following PDBu application, an excitation occurred in 28% of the group III and in 40% of the group IV fibers. An enhancement of responses to passive movements of the joint (sensitization) occurred in 37% of group III and 19% of group IV afferents. In summary, 37.5% of the low-threshold and 50% of the high-threshold fibers proved to be sensitive to PDBu. Most of the PDBu-positive units responded also to bradykinin, whereas only a few PDBu-positive units were sensitive to prostaglandin I2 and E2. We conclude from these results that, in a distinct population of slowly conducting joint afferents, protein kinase C is likely to be involved in the process of transduction. Thus, pain and hyperalgesia may be mediated at least partly by intracellular mechanisms that are linked to protein kinase C.

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

Similar content being viewed by others

References

  • Axelrod J, Burch RM, Jelsema CL (1988) Receptor-mediated activation of phospholipase A2 via GTP-binding proteins: arachidonic acid and its metabolites as second messengers. Trends Neurosci 11:117–123

    Google Scholar 

  • Bell RJ, Baenzinger NJ, Majerus DW (1980) Bradykinin-stimulated release of arachidonate from phosphatidylinositol in mouse fibrosarcoma cells. Prostaglandins 20:269–274

    Google Scholar 

  • Besson JM, Chaouch A (1987) Peripheral and spinal mechanisms of nociception. Physiol Rev 67:67–186

    Google Scholar 

  • Blair IA, Hensby CN, MacDermot J (1980) Prostacyclin-dependent activation of adenylate cyclase in a neuronal somatic cell hybrid: prostanoid structure-activity relationships. Br J Pharmacol 69:519–525

    Google Scholar 

  • Brown DA, Higashida H (1988) Inositol 1,4,5-trisphosphate and diacylglycerol mimic bradykinin effects on mouse neuroblastoma x rat glioma hybrid cells. J Physiol (Lond) 397:185–207

    Google Scholar 

  • Burgess GM, Mullaney I, McNeil M, Dunn PM, Rang HP (1989) Second messengers involved in the mechanism of action of bradykinin in sensory neurons in culture. J Neurosci 9:3314–3325

    Google Scholar 

  • Castagna M, Takai Y, Kaibuchi K, Sano K, Kikkawa U, Nishizuka Y (1982) Direct activation of calcium-activated, phospholipid-dependent protein kinase by tumor-promoting phorbol esters. J Biol Chem 257:7847–7851

    Google Scholar 

  • Conklin BR, Burch RM, Steranka LR, Axelrod J (1988) Distinct bradykinin receptors mediate stimulation of prostaglandin synthesis by endothelial cells and fibroblasts. J Pharmacol Exp Ther 244:646–649

    Google Scholar 

  • Dray A, Bettaney J, Forster P, Perkins MN (1988) Bradykinininduced stimulation of afferent fibres is mediated through protein kinase C. Neurosci Lett 91:301–307

    Google Scholar 

  • Ferreira SH, Nakamura M (1979) I-prostglandin hyperalgesia, a cAMP/Ca2+ dependent process. Prostaglandins 18:179–190

    Google Scholar 

  • Gammon CM, Allen AC, Morell P (1989) Bradykinin stimulates phosphoinositide hydrolysis and mobilization of arachidonic acid in dorsal root ganglion neurons. J Neurochem 53:95–101

    Google Scholar 

  • Garcia-Sainz JA (1991) Cell responsiveness and protein kinase C: receptors, G proteins, and membrane effectors. News Physiol Sci 6:169–173

    Google Scholar 

  • Griffiths RJ, Wood BE, Li S, Blackham A (1988) Pharmacological modification of 12-tetradecanoylphorbol-13-acetate induced inflammation and epidermal cell proliferation in mouse skin. Agents Actions 25:344–351

    Google Scholar 

  • He X, Schmidt RF, Schmittner H (1988) Effects of capsaicin on articular afferents of the cat's knee joint. Agents Actions 25:222–224

    Google Scholar 

  • He X, Schepelmann K, Schaible HG, Schmidt RF (1990) Capsaicin inhibits responses of fine afferents from the knee joint of the cat to mechanical and chemical stimuli. Brain Res 530:147–150

    Google Scholar 

  • Higashida H (1988) Acetylcholine release by bradykinin, inositol 1,4,5-triphosphate and phorbol dibutyrate in rodent neuroblastoma cells. J Physiol (Lond) 397:209–222

    Google Scholar 

  • Issandou M, Rozengurt E (1990) Bradykinin transiently activates protein kinase C in Swiss 3T3 cells. J Biol Chem 265:11890–11896

    Google Scholar 

  • Jackson TR, Hallam TJ, Downes CP, Hanley MR (1987) Receptor coupled events in bradykinin action: rapid production of inositol phosphates and regulation of cytosolic free Ca2+ in a neural cell line. EMBO J 6:49–54

    Google Scholar 

  • Juan H (1977) Mechanism of action of bradykinin-induced release of prostaglandin E. Naunyn-Schmiedeberg's Arch Pharmacol 300:77–85

    Google Scholar 

  • Kaczmarek LK (1987) The role of protein kinase C in the regulation of ion channels and neurotransmitter release. Trends Neurosci 10:30–34

    Google Scholar 

  • Kanaka R, Schaible H-G, Schmidt RF (1985) Activation of fine articular afferent units by bradykinin. Brain Res 327:81–90

    Google Scholar 

  • Kikkawa U, Kishimoto A, Nishizuka Y (1989) The protein kinase C family: heterogeneity and its implications. Annu Rev Biochem 58:31–44

    Google Scholar 

  • Lang E, Novak A, Reeh PW, Handwerker HO (1990) Chemosensitivity of fine afferents from rat skin in vitro. J Neurophysiol 63:887–901

    CAS  PubMed  Google Scholar 

  • Leach KL, Blumberg PM (1989) Tumour promoters, their receptors and their actions. In: Michell RH, Drummond AH, Downes CP (eds) Inositol lipids in cell signalling. Academic Press, New York, pp 179–205

    Google Scholar 

  • Lembeck F, Popper H, Juan H (1976) Release of prostaglandins by bradykinin as an intrinsic mechanism of its algesic effect. Naunyn-Schmiedeberg's Arch Pharmacol 294:69–73

    Google Scholar 

  • Lindsay RM, Rang HP (1988) Activation of protein kinase C causes an inward current in a proportion of rat sensory neurones in tissue culture. J Physiol (Lond) 398:16P

    Google Scholar 

  • Malhotra RK, Bhave SV, Wakade TD, Bhave AS, Wakade AR (1990) Effects of neurotransmitters and peptides on phospholipid hydrolysis in sympathetic and sensory neurons. FASEB J 4:2492–2498

    Google Scholar 

  • Meiri H, Gross B (1989) Modification of the Na-dependent action potential in myelinated fibers of rat sciatic nerve exposed to phorbol ester. Brain Res 502:401–409

    Google Scholar 

  • Miller RJ (1986) Protein kinase C: a key regulator of neuronal excitability? Trends Neurosci 9:538–541

    Google Scholar 

  • Miller RJ (1987) Bradykinin highlights the role of phospholipid metabolism in the control of nerve excitability. Trends Neurosci 10:226–228

    Google Scholar 

  • Moncada S, Mullane KM, Vane JR (1979) Prostacyclin release by bradykinin in vivo. Br J Pharmacol 66:969–979

    Google Scholar 

  • Neugebauer V, Schaible H-G, Schmidt RF (1989) Sensitization of articular afferents to mechanical stimuli by bradykinin. Pflügers Arch 415:330–335

    Google Scholar 

  • Nishizuka Y (1986) Studies and perspectives on protein kinase C. Science 233:305–312

    CAS  PubMed  Google Scholar 

  • Nishizuka Y (1988) The molecular heterogeneity of protein kinase C and its implications for cellular regulation. Nature 334:661–665

    Google Scholar 

  • Nogimori K, Kajikawa N, Nishio S, Yajima M (1989) Effects of TRK-100, a stable prostacyclin analogue, on regulation of cyclic AMP metabolism in platelets. Prostaglandins 37:205–212

    Google Scholar 

  • Oliva D, Nicosia S (1987) PGI2-receptors and molecular mechanisms in platelets and vasculature: state of the art. Pharmacol Res Commun 19:735–765

    Google Scholar 

  • Raja SN, Meyer RA, Campbell JN (1988) Peripheral mechanisms of somatic pain. Anesthesiology 68:571–590

    Google Scholar 

  • Rana RS, Hokin LE (1990) Role of phosphoinositides in transmembrane signaling. Physiol Rev 70:115–164

    Google Scholar 

  • Rang HP, Ritchie JM (1988) Depolarization of nonmyelinated fibers of rat vagus nerve produced by activation of protein kinase C. J Neurosci 8:2606–2617

    Google Scholar 

  • Rang HP, Bevan S, Dray A (1991) Chemical activation of nociceptive peripheral neurones. Br Med Bull 47:534–548

    Google Scholar 

  • Reiser G, Walter U, Hamprecht B (1984) Bradkinin regulates the level of guanosine 3′, 5′-cyclic monophosphate (cyclic GMP) in neural cell lines. Brain Res 290:367–371

    Google Scholar 

  • Roivainen R, Koistinaho J, Hervonen A (1990) Localization of protein kinase C-beta-like immunoreactivity in the rat dorsal root ganglion. Neurosci Res 7:381–384

    Google Scholar 

  • Samuelsson B, Goldyne M, Granström E, Hamberg M, Hammarström S, Malmsten C (1978) Prostaglandins and thromboxanes. Ann Rev Biochem 47:997–1029

    Google Scholar 

  • Schaible H-G, Schmidt RF (1988) Excitation and sensitization of fine articular afferents from cat's knee joint by prostaglandin E2. J Physiol (Lond) 403:91–104

    Google Scholar 

  • Schepelmann K, Meßlinger K, Schaible H-G, Schmidt RF (1992) Inflammatory mediators and nociception in the joint: excitation and sensitization of slowly conducting afferent fibers of cat's knee by prostaglandin I2. Neuroscience 50:237–247

    Google Scholar 

  • Shearman MS, Sekiguchi K, Nishizuka Y (1989) Modulation of ion channel activity: a key function of the protein kinase C enzyme family. Pharmacol Rev 41:211–237

    Google Scholar 

  • Smart RC, Huang MT, Conney AH (1986) Sn-1,2-diacylglycerol mimic the effects of 12-O-tetradecanoylphorbol-13-acetate in vivo by inducing biochemical changes associated with tumor promotion in mouse epidermis. Carcinogenesis 7:1865–1870

    Google Scholar 

  • Snider RM, Richelson E (1984) Bradykinin receptor-mediated cyclic GMP formation in a nerve cell population (murine neuroblastoma clone N1E-115). J Neurochem 43:1749–1754

    Google Scholar 

  • Taiwo YO, Levine JD (1991) Further confirmation of the role of adenyl cyclase and of cAMP-dependent protein kinase in primary afferent hyperalgesia. Neuroscience 44:131–135

    Google Scholar 

  • Taiwo YO, Bjerknes LK, Goetzl EJ, Levine JD (1989) Mediation of primary afferent peripheral hyperalgesia by the cAMP second messenger system. Neuroscience 32:577–580

    Article  CAS  PubMed  Google Scholar 

  • Yano K, Higashida H, Inoue R, Nozawa Y (1984) Bradykinin-induced rapid breakdown of phosphatidylinositol 4,5-bisphosphate in neuroblastoma x glioma hybrid NG 108–15 cells. J Biol Chem 259:10201–10207

    Google Scholar 

Download references

Author information

Author notes

  1. K. Schepelmann

    Present address: Neurologische Klinik der Universität Tübingen, Hoppe-Seyler-Str. 3, W-7400, Tübingen, Federal Republic of Germany

Authors and Affiliations

  1. Physiologisches Institut der Universität Würzburg, Röntgenring 9, W-8700, Würzburg, Federal Republic of Germany

    K. Schepelmann, K. Meßlinger & R. F. Schmidt

Authors
  1. K. Schepelmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. K. Meßlinger
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. R. F. Schmidt
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Schepelmann, K., Meßlinger, K. & Schmidt, R.F. The effects of phorbol ester on slowly conducting afferents of the cat's knee joint. Exp Brain Res 92, 391–398 (1993). https://doi.org/10.1007/BF00229027

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00229027

Key words

Search

Navigation