Elsevier

Neuroscience

Volume 93, Issue 2, July 1999, Pages 681-686
Neuroscience

Endomorphin-1 and endomorphin-2, endogenous ligands for the μ-opioid receptor, inhibit electrical activity of rat rostral ventrolateral medulla neurons in vitro

https://doi.org/10.1016/S0306-4522(99)00171-2Get rights and content

Abstract

The classic opioid peptide, enkephalin, and the novel member of the opioid family, nociceptin/orphanin FQ, inhibit the spontaneous electrical activity of neurons recorded from the rostral ventrolateral medulla, presumably cardiovascular neurons. In this study, the putative effects of endomorphin-1 and endomorphin-2, the newly discovered endogenous ligands for the μ-opioid receptor, on the electrical activity of rostral ventrolateral medulla neurons were investigated in rat brain slices in vitro. Like enkephalin and nociceptin, perfusion of endomorphin-1 or endomorphin-2 profoundly inhibited spontaneous discharges of 43% and 38% of the medullary neurons, respectively. No excitatory response to perfusion of either endomorphin was found in all neurons surveyed. Both endomorphins produced concentration-dependent inhibition. However, endomorphin-1 was more potent than endomorphin-2 for production of the inhibition, as demonstrated by the greater and longer suppression induced by endomorphin-1 than that induced by endomorphin-2 at the same concentration. Among the four opioid agonists tested, ec50 values (in nM) were 3.17 (endomorphin-1), 3.02 (nociceptin), 10.1 (endomorphin-2) and 150.0 (enkephalin). The non-selective opioid receptor antagonist, naloxone, blocked the inhibitory responses of the neurons to endomorphin-1, endomorphin-2 and enkephalin, but not to nociceptin. The selective μ antagonist, β-funaltrexamine, prevented the neuronal inhibition induced by endomorphins, but not by enkephalin and nociceptin. Neither naloxone nor β-funaltrexamine alone had a significant effect on the firing rate of the neurons.

These results demonstrate that endomorphin-1 and, to a lesser extent, endomorphin-2 exert an inhibitory modulation of the electrical activity of rostral ventrolateral medulla neurons, which is mediated through the stimulation of μ-opioid receptors.

Section snippets

Animals

Male Sprague–Dawley rats weighing 100–150 g (Animal Facility of Shanghai Medical University, PRC) were used in this study. Before use, rats were housed three or four to a clear plastic cage and maintained on a 12-h/12-h light/dark schedule, with food and water provided ad libitum. All animal use procedures were in strict accordance with the NIH Guide for the Care and Use of Laboratory Animals.

Single-unit recording in brain slices

Recording of single-unit discharge in rat brain slices containing the RVLM was conducted according to

Effects of endomorphin-1 and endomorphin-2 perfusion on firing rate of rostral ventrolateral medulla neurons

In this study, we recorded a total of 78 units with spontaneous firing activity in the RVLM region. The spontaneous activity was either regular or irregular, with a range of 2–26 Hz (mean±S.E.M.: 8.3±1.6 Hz). Among these neurons, we then tested the effects of EM-1 and EM-2 perfusion on neuronal firing rate in 65 and 42 units, respectively. Following EM-1 perfusion at a concentration of 10 nM, spontaneous discharges of 43% (28 of 65) of neurons were nearly abolished (see a representative recording

Discussion

Single-unit recording from rat brain slices was utilized to explore the effects of EM-1 and EM-2 on the electrical activity of the CNS neurons. We found that EM-1 and EM-2 perfusion considerably inhibited the spontaneous firing frequency of 43% and 38% of neurons recorded from the RVLM region, respectively. Both endomorphins produced this suppression in a concentration-dependent manner. However, EM-1 was approximately threefold more potent than EM-2 in depressing RVLM neuronal firing. The

Conclusion

The effects of EM-1 and EM-2, the recently isolated endogenous ligands for the μ-opioid receptor, on the electrical activity of neurons recorded from the RVLM in rat brain slices were investigated in this study. Like other opioid peptides (met-ENK and nociceptin), both EM-1 and EM-2 concentration-dependently inhibited the spontaneous discharges of RVLM neurons. In this action, EM-1 was more potent than EM-2, as EM-1-induced suppression was greater and longer than that induced by EM-2 at all

Acknowledgements

This work was supported, in part, by grants 39570272 (to P.L.) from the National Nature Science Foundation of China and the National Key Lab of Medical Neurobiology of China, and 9960266Z (to J.Q.W.) from the American Heart Association. We wish to thank Dr Y. X. Cao for technical assistance.

References (34)

  • S.Y Sun et al.

    Central effects of opioid agonists and naloxone on blood pressure and heart rate in normotensive and hypertensive rats

    Gen. Pharmac.

    (1996)
  • H Akil et al.

    Endogenous opioids: biology and functions

    A. Rev. Neurosci.

    (1984)
  • B Anton et al.

    Immunohistochemical localization of ORL-1 in the central nervous system of the rat

    J. comp. Neurol.

    (1996)
  • U Arvidsson et al.

    δ-Opioid receptor immunoreactivity: distribution in brainstem and spinal cord, and relationship to biogenic amines and enkephalin

    J. Neurosci.

    (1995)
  • U Arvidsson et al.

    Distribution and targeting of a μ-opioid receptor (MOR1) in brain and spinal cord

    J. Neurosci.

    (1995)
  • H.C Champion et al.

    The endogenous μ-opioid agonists, endomorphins 1 and 2, have vasodilator activity in the hindquarter vascular bed of the rat

    Life Sci.

    (1997)
  • V Chapman et al.

    Distinct inhibitory effects of spinal endomorphin-1 and endomorphin-2 on evoked dorsal horn neuronal responses in the rat

    Br. J. Pharmac.

    (1997)
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