Summary
The antinociceptive effect of subcutaneously (s. c.), intracerebroventricularly (i.c.v.) or intrathecally (i.t.) administered diclofenac was studied in a series of experiments employing the tail-flick (0.01–10.0 mg/kg body weight i. p., 1–50 μg i.c.v., 1–10 μg i.t.) and hotplate (0.01–50 mg/kg body weight i. p., 1– 50 μg i. c. v., 1–10 μg i. t.) models representing somatosensory stimuli and the writhing test (0.001 mg–10 mg s. c., 0.1–200 μg i.c.v., 0.1–100 μg i. t.) and colorectal distension (1–200 μg i.c.v.) models representing noxious visceral stimuli. Diclofenac did not exert any antinociceptive effects in the tail-flick or hot-plate models. In the writhing test, diclofenac dose-dependently inhibited the number of writhings after s. c. administration (0.001–10.0 mg/kg body weight) with an ED50 of 1 mg/kg. A similar dose-dependent action of diclofenac was seen after i.c.v. (0.1–200 μg) and i.t. (0.1–100 μg) administration with an ED50 of 3 α in both cases. The antinociceptive effect of diclofenac administered s. c., i.c.v. or i.t. was almost completely reversed by pretreatment with naloxone, (1 mg/kg body weight s. c.).
In the colorectal distension model, the i.c.v. administration of diclofenac (1–200 μg), which attenuated the cardiovascular response to colorectal distension, was reversed by naloxone. The pressor and tachycardia response to a 20 s, 80 mmHg colorectal distension was inhibited by diclofenac 100 μg i.c.v. (16.1 ± 1.7 mmHg or 58% and 39.4 ± 0.4 bpm or 70% versus control, respectively).
It is concluded that diclofenac exerts a central, naloxone-reversible antinociceptive action in experimental animals after noxious visceral stimuli but not after somatosensory stimuli.
Similar content being viewed by others
References
Carlsson KH, Helmreich J, Jurna I (1986) Activation of inhibition from periaqueductal grey matter mediates central analgesic effect of metamizol (Dipyrone). Pain 27:373–390
Carlsson KH, Monzel W and Jurna I (1988) Depression by morphine and the non-opioid analgesic agents metamizol (Dipyrone), lysine acetylate and paracetamol, of activity in rat thalamus neurons evoked by electrical stimulation of nociceptive afferents. Pain 32:313–326
D'Amour FE, Smith DL (1941) A method for determining loss of pain sensation. J Pharm Exp Ther 72:74–79
Deraedt R, Jonquey S, Delevallée F, Flahaut M (1980) Release of ] prostaglandins E and F in an algogenic reaction and its inhibition. Eur J Pharmacol 61:17–24
Ferreira SH, Lorenzetti BB, Corréa FMA (1978) Central and peripheral antialgesic action of aspirin-like drugs. Eur J Pharmacol 53:39–48
Garcia-Sevilla JA, Ahtee L, Magnusson T, Carlsson A (1978) Opiate-receptor mediated changes in monoamine synthesis in rat brain. J Pharm Pharmcol 30:613–621
Gerra G, Ceresini, Rastelli G, Butturini L, Vescovi PP (1985) Effect of diclofenac on the opiate withdrawal syndrome. G Clin Med 66:459–465
Grossmann W, Jurna I, Nell T, Theres C (1973) The dependence of the anti-nociceptive effect of morphine and other analgesic agents on spinal motor activity after central monoamine depletion. Eur J Pharmacol 24:67–77
Hendershot LC, Forsaith J (1959) Antagonism of the frequency of phenylquinone-induced writhing in the mouse by weak analgesics and nonanalgesics. J Pharmacol Exp Ther 125:237–240
Holmgren M, Hedner J, Mellstrand T, Nordberg G, Hedner T (1986) Characterization of the antinociceptive effects of some adenosine analogues in the rat. Naunyn-Schmiedeberg's Arch Pharmacol 334:290–293
Jaques R (1977) Antagonism of non-steroidal anti-inflammatory drugs and narcotic analgesics against etacrynic acid induced writhing. Arzneimittel Forschung 27:1698–1700
Lim RKS, Guzman F (1968) Manifestations of pain in analgesic evaluation in animals and man. Academic Press, London, pp 119–152
Lopachin RM, Rudy TA, Yaksh TL (1981) An improved method for chronic catheterization of the rat spinal subarachnoid space. Physiol Behav 27:559–561
Martini A, Bondiolotti GP, Sacerdote P, Pierro L, Picotti GB, Panerai AE, Restelli L, Zancaner F, Monza G (1984) Diclofenac increases B-endorphin plasma concentrations. J Int Med Res 12:92–95
Martorano AD, Di Chiara A, Speciale R, Palermo R, Luciano A, Di Stefano S (1984) Trattamento con diclofenac sodico nel dolore post-operatoria e oppioidi endogeni. Argomenti Di Chirurgia 4:181–187
Menassé R, Hedwall PR, Kraetz J, Pericin C, Riesterer L, Sallmann A, Ziel R, Jaques R (1978) Pharmacological properties of diclofenac sodium and its metabolites. Scand J Rheumatol Suppl 22:5–16
Ness TJ, Gebhart GF (1988) Colorectal distension as a noxious visceral stimulus: physiologic and pharmacologic characterization of pseudoaffective reflexes in the rat. Brain Res 450:153–169
Okuyama S, Aihara H (1984) The mode of action of analgesic drugs in adjuvant arthritic rats as an experimental model of chronic inflammatory pain: Possible central analgesic action of acidic nonsteroidal anti-inflammatory drugs. Jpn J Pharmacol 35:95–103
Okuyama S, Aihara H (1986) Hyperalgesic action in mice of intracerebroventricularly administered arachidonic acid, PGE2, PGF2a and PGD2: Effects of analgesic drugs on hyperalgesia. J Pharmacobiodyn 9:902–908
Sacerdote P, Monza G, Mantegazza P, Panerai AE (1985) Diclofenac and pirprofen modify pituitary and hypothalamic beta-endorphin concentrations. Pharmacol Res Commun 17:679–684
Shaligram SV, Nabar SD (1987) Sites of anti-writhing effect of salicylate. Xth Internat Congr Pharm, Sydney, Australia, poster 825
Shyu KW, Lin MT, Wu TC (1984) Possible role of central serotonergic neurons: in the development of dental pain and aspirin-induced analgesia in the monkey. Exp Neurol 84:179–187
Shyu KW, Lin MT (1985) Hypothalamic monoaminergic mechanisms of aspirin-induced analgesia in monkeys. J Neural Transm 62:285–293
Siegmund E, Cadmus R, Lu G (1957a) A method for evaluating both non-narcotic and narcotic analgesics. Proc Soc Exp Biol Med 95:729–731
Siegmund E, Cadmus R, Lu G (1957b) Screening of analgesics, including aspirin-type compounds, based upon the antagonism of chemically induced “writhing” in mice. J Pharmacol Exp Ther 119:184
Stephens RJ (1984) Evidence for a pharmacokinetic interaction between ibuprofen and meptazinol in the mouse. J Pharmacol Exp Ther 36:779–781
Vescovi P, Passeri M, Gerra G, Grossi E (1987) Naloxone inhibits the early phase of diclofenac analgesia in man. The Pain Clinic 1:151–155
Willer J-C, De Broucker T, Bussel B, Roby-Brami A, Harrewyn J-M (1989) Central analgesic effect of ketoprofen in humans: electrophysiological evidence for a supraspinal mechanism in a double-blind and cross-over study. Pain 38:1–7
Woolfe G, MacDonald AD (1944) The evaluation of analgesic action of pethidine hydrochloride (Demerol). J Pharmacol Exp Ther 80:300–307
Vyklicky L (1984) Methods of testing pain mechanisms in animals. In: Wall PD, Melzack R (eds) Textbook of pain. Churchill Livingstone, Edinburgh London; Raven Press, New York, pp 178–185
Yaksh TL (1976) Chronic catheterization of the spinal subarachnoid space. Physiol Behav 17:1031–1036
Yaksh TL (1982) Central and peripheral mechanisms for the antialgesic action of acetylsalicylic acid. Raven Press, New York, pp 137–151
Yaksh TL (1984a) Multiple opioid receptor systems in brain and spinal cord. Part I. Eur J Anaesthesiol 25:171–199
Yaksh TL (1984b) Multiple opioid receptor systems in brain and spinal cord. Part 2. Eur J Anaesthesiol 21:201–243
Author information
Authors and Affiliations
Additional information
Send offprint requests to R. Bjorkman at the above address
Rights and permissions
About this article
Cite this article
Björkman, R., Hedner, J., Hedner, T. et al. Central, naloxone-reversible antinociception by diclofenac in the rat. Naunyn-Schmiedeberg's Arch Pharmacol 342, 171–176 (1990). https://doi.org/10.1007/BF00166960
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00166960