Research reportOpioid receptors on peripheral sensory axons
Introduction
Opiate receptors are manufactured by primary sensory neurons (dorsal root ganglion or DRG cells) and transported centrally [7]. The spinal actions of opiates, presumably acting on these receptors, have been extensively studied 27, 33. Opiate receptors have also been demonstrated peripherally in fine cutaneous nerves by light microscopic techniques 13, 29. Important physiologic effects of peripheral opiates are that they raise the withdrawal threshold to nociceptive mechanical stimuli if the perineurial barrier is disrupted [1]and relieve inflammatory pain 28, 29, 30. Left unanswered in these studies is whether the structures in the nerves that contain opiate receptors are unmyelinated axons and, if they are, what percentage of these fibers express these receptors. Furthermore, it is unclear whether opioid receptors have any action in nociceptive or physiologic (non-inflammatory) pain 1, 16. Accordingly the present study is an electron microscopic analysis of cutaneous sensory axons immunostained for opioid receptors followed by an analysis of the effects of opioids on the behavioral responses to peripherally injected glutamate which causes pain-related behavior [6]unaccompanied by signs of inflammation.
Section snippets
Anatomical assays
Male Sprague–Dawley rats (125–200 g, n=3) were deeply anesthetized with nembutal and perfused through the aorta with heparinized saline followed by a mixture of 2.5% glutaraldehyde, 1.0% paraformaldehyde and 0.1% picric acid (v/v of saturated aqueous solution) in 0.1 M phosphate buffer at 4°C. Glabrous skin was removed from the plantar surface of the third hind toe and cut into small blocks (approximately 100 μm). Each block was immunostained with the ABC method (Vector Labs) using a previously
Anatomical studies
Immunostaining with the MOR or DOR antibodies resulted in labeling of unmyelinated axons which are located in bundles in the dermal-epidermal region (Fig. 1). A few myelinated axons that could be seen in nerves deeper in the dermis were also labeled. Due to the scarcity of myelinated fibers in these locations, however, only the percentages of labeled unmyelinated axons were determined. Antibodies directed against the MOR and the DOR resulted in 29±7% and 38±0% (mean±S.E.) respectively, of
Discussion
The major findings of the present study are that 29–38% of peripheral cutaneous unmyelinated axons in rat glabrous skin are immunostained for μ- or δ-opioid receptors and that an exogenous μ- but not a δ-opioid ligand applied peripherally attenuates the pain-related behaviors following local injection of GLU, a non-inflammatory noxious stimulus. Many studies show opioid receptors on DRG neurons 2, 3, 21and concentrated in lamina II in the dorsal horn 4, 5, 8, 11, 23, where central terminals of
Acknowledgements
This work was supported by NS11255 (R.E.C., S.M.C.), NS27910 (S.M.C.) and NS10161 (R.E.C.). We wish to thank Zhixia Ding for excellent technical assistance with the immunostaining and electron microscopy and Brenda Kenworthy and Lyn Schilling for their excellent secretarial support.
References (34)
- et al.
Autoradiographic localization of opiate receptors in rat brain. I. Spinal cord and lower medulla
Brain Res.
(1977) - et al.
Autoradiographic distribution of μ, δ, and κ opioid binding sites in the superficial dorsal horn, over the rostrocaudal axis of the rat spinal cord
Brain Res.
(1991) - et al.
Localization and activation of glutamate receptors in unmyelinated axons of rat glabrous skin
Neurosci. Lett.
(1995) - et al.
Effects of enkephalin, applied intracellularly, on action potentials in vertebrate A and C nerve fibre axons
Neuropharmacology
(1987) - et al.
Inflammation of the rat paw enhances axonal transport of opioid receptors in the sciatic nerve and increases their density in inflamed tissue
Neuroscience
(1993) - et al.
Peripheral opioid modulation of pain and inflammation in the formalin test
Eur. J. Pharmacol.
(1995) - et al.
The effect of morphine on mammalian nerve fibers
Eur. J. Pharmacol.
(1977) - et al.
Potent and long lasting antinociceptive effects after injection of low doses of a mu-opioid receptor agonist, fentanyl, into the brachial plexus sheath of the rat
Pain
(1990) - et al.
Use of high concentration of glutaraldehyde for immunocytochemistry of transmitter-synthesizing enzymes in the central nervous system
Neuroscience
(1986) - et al.
Opiate receptor binding in primate spinal cord: distribution and changes after dorsal root section
Brain Res.
(1976)
Involvement of the mu-opiate receptor in peripheral analgesia
Neuroscience
Immunohistochemical localization of the cloned mu opioid receptor in the rat CNS
J. Chem. Neuroanat.
Double in situ hybridization study on coexistence of μ-, δ- and κ-opioid receptor mRNAs with preprotachykinin A mRNA in the rat dorsal root ganglia
Mol. Brain Res.
Localization of opiate and histamine H1-receptors in the primate sensory ganglia and spinal cord
Brain Res.
Effect of dorsal rhizotomy on the autoradiographic distribution of opiate and neurotensin receptors and neurotensin-like immunoreactivity within rat spinal cord
Brain Res.
Lack of opiate effects on cat C polymodal nociceptive fibers
Pain
Narcotic analgetics: CNS sites and mechanisms of action as revealed by intracerebral injection techniques
Pain
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