Elsevier

Brain Research

Volume 764, Issues 1–2, 1 August 1997, Pages 126-132
Brain Research

Research report
Opioid receptors on peripheral sensory axons

https://doi.org/10.1016/S0006-8993(97)00446-0Get rights and content

Abstract

Opioid receptors have been demonstrated by light microscopic techniques in fine cutaneous nerves in naive animals. The present study extends these findings by showing that 29 and 38% of unmyelinated cutaneous sensory axons can be immunostained for μ- or δ-opioid receptors respectively. Local cutaneous injection of DAMGO, a μ-opioid ligand, ameliorates the nociceptive behaviors caused by local cutaneous injection of glutamate, a purely nociceptive chemical stimulus showing that the μ-receptors are functional. By contrast the δ-opioid ligand [2-d-penicillamine, 5-d-penicillamine]enkephalin (DPDPE) had no effect on these behaviors. These findings indicate a wider function for opioid receptors in naive animals than previously envisioned.

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)

Cited by (211)

  • Immune cell-mediated opioid analgesia

    2020, Immunology Letters
    Citation Excerpt :

    Therefore, in the following sections, we focus on mu-, delta-, and kappa-receptors. All three receptors are synthetized in dorsal root ganglia (DRG) small-, medium- and, to a lesser degree, large-diameter neurons [14–18], are transported to [19–22] and accumulate at their peripheral terminals [23–26]. Opioid receptors are also expressed in neurons of trigeminal and nodose ganglia, and submucosal and myenteric plexuses of the enteric nervous system in the gastrointestinal tract [14,21,27].

View all citing articles on Scopus
View full text