Hostname: page-component-78c5997874-s2hrs Total loading time: 0 Render date: 2024-11-15T17:15:59.239Z Has data issue: false hasContentIssue false
  • English
  • Français

Supraspinal and spinal cord opioid receptors are responsible for antinociception following intrathecal morphine injections

Published online by Cambridge University Press:  23 December 2004

C. S. Goodchild ,
R. Nadeson  and
E. Cohen
C. S. Goodchild
Affiliation:
Monash University Department of Anaesthesia, Monash Medical Centre, Clayton, Victoria, Australia
R. Nadeson
Affiliation:
Monash University Department of Anaesthesia, Monash Medical Centre, Clayton, Victoria, Australia
E. Cohen
Affiliation:
Monash University Department of Anaesthesia, Monash Medical Centre, Clayton, Victoria, Australia
Get access

Abstract

Summary

Background and objective: The clinical practice of spinal morphine administration for pain relief is based on observations in animals that opioid receptors exist in the spinal cord and intrathecal injections of opioids in those species (mostly rats) lead to antinociceptive effects. Clinicians are well aware that administration of spinal opioids is associated with side-effects, such as nausea and respiratory depression, that indicate supraspinal spread of the drug administered. Those observations call into question how much of the observed pain relief is due to action of the drug in the brain. This study investigated the spinal cord actions of morphine given intrathecally to rats in a model that allows investigation of drug–receptor interaction at the spinal cord level. Experiments were performed on male Wistar rats with chronically implanted lumbar subarachnoid catheters.

Methods: Nociceptive thresholds were measured in rats given morphine intrathecally alone and in combination with intrathecal injections of selective opioid receptor antagonists: β-funaltrexamine (μ), naltrindole (δ) and nor-binaltorphimine (κ).

Results: Intrathecal morphine caused dose-related antinociceptive effects that were reversed totally by naloxone. Intrathecal β-funaltrexamine and naltrindole did not reverse the effects of intrathecal morphine. However, intrathecal nor-binaltorphimine did reverse the electrical current threshold effects of morphine but not tail flick latency.

Conclusions: Antinociception following intrathecal morphine involves spinal and supraspinal opioid receptors. The tail flick effect described in rat experiments involves actions at opioid receptors in the brain that override any action that may be caused by combination of morphine with μ-opioid receptors in the spinal cord.

Keywords

ANALGESICS, opioidCENTRAL NERVOUS SYSTEM, SPINAL CORDINJECTIONS, spinalPAIN, measurementRECEPTORS, neurotransmitter
Type
Original Article
Information
European Journal of Anaesthesiology , Volume 21 , Issue 3 , March 2004 , pp. 179 - 185
Copyright
2004 European Society of Anaesthesiology

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Yaksh TL, Rudy TA. Analgesia mediated by a direct spinal action of narcotics. Science 1976; 192: 1357–1358.Google Scholar
Wang JK, Nauss LA, Thomas JE. Pain relief by intrathecally applied morphine in man. Anesthesiology 1979; 50: 149–151.Google Scholar
Cousins MJ, Mather LE. Intrathecal and epidural administration of opioids. Anesthesiology 1984; 61: 276–310.Google Scholar
Andersen G, Rasmussen H, Rosenstock C, et al. Postoperative pain control by epidural analgesia after trans-abdominal surgery – efficacy and problems encountered in daily routine. Acta Anaesthesiol Scand 2000; 44: 296–301.Google Scholar
Angst MS, Ramaswamy B, Riley ET, Stanski DR. Lumbar epidural morphine in humans and supraspinal analgesia to experimental heat pain. Anesthesiology 2000; 92: 312–324.Google Scholar
Bernards CM. Rostral spread of epidural morphine – the expected and the unexpected. Anesthesiology 2000; 92: 299–301.Google Scholar
Chaney MA. Side effects of intrathecal and epidural opioids. Can J Anesth 1995; 42: 891–903.Google Scholar
Kingery WS. A critical review of controlled clinical trials for peripheral neuropathic pain and complex regional pain syndromes. Pain 1997; 73: 123–139.Google Scholar
Rawal N, Allvin R, Neumark J, et al. Epidural and intrathecal opioids for postoperative pain management in Europe – a 17-nation questionnaire study of selected hospitals. Acta Anaesthesiol Scand 1996; 40: 1119–1126.Google Scholar
Buerkle H, Yaksh TL. Comparison of the spinal actions of the μ-opioid remifentanil with alfentanil and morphine in the rat. Anesthesiology 1996; 84: 94–102.Google Scholar
Borgbjerg FM, Frigast C, Madsen JB, Mikkelsen LF. The effect of intrathecal opioid-receptor agonists on visceral noxious stimulation in rabbits. Gastroenterol 1996; 110: 139–146.Google Scholar
Guirimand F, Strimbu-Gozariu M, Willer JC, Le Bars D. Effects of mu, delta and kappa opioid antagonists on the depression of a C-fiber reflex by intrathecal morphine and DAGO in the rat. J Pharmacol Exp Ther 1994; 3: 1007–1020.Google Scholar
Hammond DL, Wang HL, Nakashima N, Basbaum AI. Differential effects of intrathecally administered delta and mu opioid receptor agonists on formalin-evoked nociception and on the expression of Fos-like immunoreactivity in the spinal cord of the rat. J Pharmacol Exp Ther 1998; 284: 378–387.Google Scholar
Hara K, Saito Y, Kirihara Y, Yamada Y, Sakura S, Kosaka Y. The interaction of antinociceptive effects of morphine and GABA receptor agonists within the rat spinal cord. Anesth Analg 1999; 89: 422–427.Google Scholar
Yaksh TL, Rudy TA. Chronic catheterization of the spinal subarachnoid space. Phys Behav 1976; 17: 1031–1036.Google Scholar
Irwin S, Houde RW, Bennett DR, Hendershot LC, Seevers MH. The effects of morphine, methadone and meperidine on some reflex responses of spinal animals to nociceptive stimulation. J Pharmacol Exp Ther 1950; 101: 132–143.Google Scholar
Heinricher MM, Drasner K. Lumbar intrathecal morphine alters activity of putative nociceptive modulatory neurons in rostral ventromedial medulla. Brain Res 1991; 549: 338–341.Google Scholar
Glynn CJ, Mather LE, Cousins MJ, Wilson PR, Graham JR. Spinal narcotics and respiratory depression. Lancet 1979; 2: 356–357.Google Scholar
Liolios A, Anderson FH. Selective spinal analgesia. Lancet 1979; 2: 357.Google Scholar
Reiz S, Westberg M. Side-effects of epidural morphine. Lancet 1980; 2: 203–204.Google Scholar
Baraka A, Noueihid R, Hajj S. Intrathecal injection of morphine for obstetric analgesia. Anesthesiology 1981; 54: 136–140.Google Scholar
Gustafsson LL, Schildt B, Jacobsen K. Adverse effects of extradural and intrathecal opiates; report of a nationwide survey in Sweden. Br J Anaesth 1998; 81: 86–93.Google Scholar
Yaksh TL. Spinal opiate analgesia; characteristics and principles of action. Pain 1981; 11: 293–346.Google Scholar
Goodchild CS, Guo Z, Freeman J, Gent JP. 5-HT spinal antinociception involves mu opioid receptors; cross tolerance and antagonist studies. Br J Anaesth 1997; 78: 563–569.Google Scholar
Zimmerman M. Ethical guidelines for investigation of experimental pain on conscious animals. Pain 1983; 16: 109–110.Google Scholar
Edwards M, Serrao JM, Gent JP, Goodchild CS. On the mechanism by which midazolam causes spinally mediated analgesia. Anesthesiology 1990; 73: 273–277.Google Scholar
Nadeson R, Guo Z, Porter V, Gent JP, Goodchild CS. GABAA receptors and spinally-mediated antinociception in rats. J Pharmacol Exp Ther 1996; 278: 620–626.Google Scholar
Serrao JM, Stubbs SC, Goodchild CS, Gent JP. Intrathecal midazolam and fentanyl in the rat; evidence for different spinal antinociceptive effects. Anesthesiology 1989; 70: 780–786 (erratum Anesthesiology 1989; 71: 482).Google Scholar
Boulter N, Serrao JM, Gent JP, Goodchild CS. Spinally mediated antinociception following intrathecal chlordiazepoxide – further evidence for a benzodiazepine spinal analgesic effect. Eur J Anaesthesiol 1991; 8: 407–411.Google Scholar
Goodchild CS, Guo Z, Musgreave A, Gent JP. Antinociception by intrathecal midazolam involves endogenous neurotransmitters acting at spinal cord delta opioid receptors. Br J Anaesth 1996; 77: 758–763.Google Scholar
Goodchild CS, Sanghera S, Serrao JM, Gent JP. Analgesia mediated by spinal κ-opioid receptors. Eur J Anaesthesiol 1991; 8: 227–231.Google Scholar
Yaksh TL, Rudy TA. Studies on the direct spinal action of narcotics in the production of analgesia in the rat. J Pharmacol Exp Ther 1977; 202: 411–428.Google Scholar
Carroll MN, Lim RKS. Observations on the neuropharmacology of morphine and morphine-like analgesia. Arch Int Pharmacodyn Ther 1960; 125: 383.Google Scholar
Yaksh TL, Henry JL. Antinociceptive effects of intrathecally administered human b-endorphin in the rat and cat. Can J Physiol Pharmacol 1978; 56: 754–759.Google Scholar
Yu W, Hao JX, Xu XJ, Hökfelt T, Elde R, Wiesenfeld-Hallin Z. Spinal cord ischemia reduces μ-opioid receptors in rats; correlation with morphine insensitivity. Neuroreport 1999; 10: 87–91.Google Scholar
Zhang X, Bao L, Shi TJ, Ju G, Elde R, Hokfelt T. Down-regulation of μ-opioid receptors in rat and monkey dorsal root ganglion neurons and spinal cord after peripheral axotomy. Neuroscience 1987; 82: 223–240.Google Scholar
Loh HH, Liu HC, Cavalli A, Yang W, Chen YF, Wei LN. Mu opioid receptor knockout in mice; effects on ligand-induced analgesia and morphine lethality. Brain Res Mol Brain Res 1998; 54: 321–326.Google Scholar
Matthes HW, Maldonado R, Simonin F, et al. Loss of morphine-induced analgesia, reward effect and withdrawal symptoms in mice lacking the mu-opioid-receptor gene. Nature 1996; 383: 819–823.Google Scholar
Narita M, Mizoguchi H, Sora I, Uhl GR, Tseng LF. Absence of G-protein activation by mu-opioid receptor agonists in the spinal cord of mu-opioid receptor knockout mice. Br J Pharmacol 1999; 126: 451–456.Google Scholar
Pasternak GW. Incomplete cross tolerance and multiple mu opioid peptide receptors. Trends Pharmacol Sci 2001; 22: 67–70.Google Scholar
Schuller AG, King MA, Zhang J, et al. Retention of heroin and morphine-6 beta-glucuronide analgesia in a new line of mice lacking exon 1 of MOR-1. Nat Neurosci 1999; 2: 151–156.Google Scholar
Sora I, Takahashi N, Funada M, et al. Opiate receptor knockout mice define mu receptor roles in endogenous nociceptive responses and morphine-induced analgesia. Proc Natl Acad Sci USA 1997; 94: 1544–1549.Google Scholar