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The effects of opioids on the peripheral terminals of rat and guinea pig sensory neurons

Ketchum, Steven Blake; (1990) The effects of opioids on the peripheral terminals of rat and guinea pig sensory neurons. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Studies in vivo and in vitro suggest that opioids can modulate nociceptive signals by interacting with receptors on peripheral neurons. We investigated the peripheral actions of mu (μ), delta (δ), and kappa (κ) opioid agonists using an electrophysiological model of inflammatory-type nociception. Dorsal horn convergent neurons were recorded extracellularly in the halothane anesthetized intact adult rat. Subcutaneous injection of formalin into the hindpaw receptive field of these neurons results in two distinct phases of cell firing. Neither morphine, exogenous ligand for the μ receptor, nor the δ agonist Tyr-D-Ser-(tbu)-Gly-Phe-Leu-Thr (DSTBULET) influenced the formalin response when administered peripherally into the paw. The κ-selective ligand U50488H produced a dose-dependent, naloxone-reversible inhibition of both phases of formalin-induced activity which does not result from leakage of the drug into the systemic circulation. Intrathecal administration of μ and δ, but not κ, opioids has previously been shown to inhibit the biphasic formalin response in the adult rat. Our data suggest that different types of opioid receptors may be important in the periphery and spinal cord. There is some indication that opioid receptor populations are different in adult and neonatal rat spinal cord. For example there are functional μ and κ, but not δ, opioid receptors in an in vitro model of nociceptive activity in the neonatal rat spinal cord. We looked at these apparent developmental differences in binding assays in which opioid receptors in the two tissues were characterized by measurements of ligand binding to crude membrane fractions. Results from binding studies agreed well with fictional studies, in that δ opioid binding sites were not detected on neonatal rat spinal cord membranes. Levels of κ binding were higher in the neonate than in the adult. Novel continuous clonal cell lines with some characteristics of nociceptive dorsal root ganglion (DRG) neurons were tested as a potential model system for the action of opioids on primary afferent nerve fibers. Two of the cell lines expressed δ, but not μ or κ, opioid binding sites. We could not detect effects of δ opioids on potassium currents (as measured by 86Rubidium efflux) or on the release of substance P-like immunoreactivity (SP-LI). We concluded that these cell lines were not good models for studying opioid action on sensory neurons. Measurement of SP-LI release from guinea pig cardiac right ventricular slices did provide a useful model to study peripheral actions of opioids. Formalin (0.2%), capsaicin (100 nM-3μM), and a depolarizing concentration of potassium (100 mM K+) increased the outflow of SP-LI from heart slices. Agonists at μ, δ, and κ opioid receptors inhibited K+-stimulated release and these effects were reversed by naloxone to differing degrees. High concentrations of μ and κ ligands, in their own right, increased the outflow of SP-LI, and these results are compared to previous reports of opioid excitation. Formalin-evoked SP-LI release from heart slices was subject to modulation by opioids. These results agreed well with in vivo results, in that SP-LI release evoked by formalin was not inhibited by μ or δ opioid agonists, but was sensitive to blockade by the κ ligand U50488H. We have demonstrated effects of opioids on the peripheral terminals of sensory neurons in two different models. Peripheral κ, but not μ or δ, receptors were important in modulating formalin-induced effects both in vivo and in vitro. Central κ receptors, at least in adult rats, have been shown not to influence the formalin response in vivo to the same extent as μ and δ receptors. In vitro μ, δ, and κ opioids modulated responses to K+ depolarization of sensory neurons at the peripheral terminals. These results provide strong evidence that peripheral opioid receptors can modulate nociceptive signals.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: The effects of opioids on the peripheral terminals of rat and guinea pig sensory neurons
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Biological sciences; Opioid agonists
URI: https://discovery.ucl.ac.uk/id/eprint/10121048
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