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Histol Histopathol (1 998) 13: 955-959 http://www.ehu.es/histol-histopathol Histology and Histo pathology Modifications in the distribution of met-enkephalin in the cat spinal cord after administration of clonidine. An immunocytochemical study J. Vazquezl, R. Covenas2, M. Muiioz3, J.A. Garcia3 and A. Victoria4 Department of Morphological Sciences. School of Medicine, University of Sevilla, Sevilla, 2Department of Cell Biology and Pathology, School of Medicine, University of Salamanca, Salamanca, 3Service of Pediatry, Children's Hospital, Sevilla and 4Department of Morphological Sciences, School of Medicine, University of Valencia, Valencia, Spain Summary. We have studied the modifications in the distribution of methionine-enkephalin in the cat spinal cord after intravenous or intrathecal administration of clonidine by using an immunocytochemical technique. In animals not treated with the substance, a very high density of immunoreactive fibers was found in layers I and 11; a high density in the dorso-lateral funiculus and in the reticular formation; a moderate density in layers 111, IV and V; and a low density in layer VI. However, after intravenous or intrathecal administration of clonidine a decrease in fibers containing met-enkephalin was observed in layers I and I1 (high or moderate density), the dorso-lateral funiculus, and the reticular formation (moderate or low density), and in layers IV and V (low or very low density). In all cases, the decrease in the immunoreactivity was more marked when clonidine was administered intrathecally. Our results suggest that clonidine induces the release of metenkephalin in the spinal cord. They further suggest that the opioid peptide released could be involved in the control of nociceptive transmission by inhibiting the release of neurotransmitters (e.g., substance P). In summary, our study shows that clonidine could be involved in antinociceptive mechanisms in the cat spinal cord. Key words: Met-cnkephalin, Clonidine, Spinal cord, ~mmunocytochemistr~, Cat Introduction Pain is the most important human clinical symptom and a very unpleasant experience whose solution remains to be solved. The discovery and localization of endogenous opioid peptides in the nervous system Offprint requests to: Prof. Dr. Jose Vazquez, Departamento de Ciencias Morfologicas, Facultad de Medicina, Universidad de Sevilla. Avda. Sanchez Pizjuan s/n, 41009-Sevilla, Spain (Hughes et al., 1975; Guillemin et al., 1976; ConrathVerrier et al., 1983; Conrath et al., 1986) has opened new therapeutic possibilities for reducing the sensation of pain, since if endogenous peptides with opioid activity could be released by means of psychic, physical or pharmacological stimuli, it seems that this release of peptides could produce analgesia without any secondary effects. In this sense, after low-frecuency analgesic electroacupuncture, several studies have shown alterations in the distribution of met-cnkephalin in the cat central nervous system (Vizquez et al., 1995) especially at sites related to nociceptive pathways (Vacca-Galloway et al., 1985; Cobos, 1988; Vazquez et al., 1990). In the present study we searched for changes in the enkephalinergic system of the cat spinal cord using a chemical stimulus; namely, clonidine. We chose this substance because it has been demonstrated, a) to have a potent analgesic effect (Yaksh and Reddy, 1981; Nakamura and Lico, 1988; Mastrianni et al., 1989; Ossipov et al., 1989), and b) to be very efficient as treatment during the opioid withdrawal syndrome (Tseng et al., 1975; Gold and Pottasch, 1981). Clonidine apparently produces analgesia by releasing methionine-enkephalin from the terminals, inhibiting this neuroactive substance the release of neurotransmitters (e.g., substance P) in the nociceptive pathways (Jessel and Iversen, 1977). Moreover, it seems that during the opioid withdrawal syndrome, clonidine administration restores the normal levels of opiate peptides that are decreased, because their synthesis would be blocked by exogenous opioid peptide administration. The aims of this work were therefore: 1) to compare the density of fibers containing met-enkephalin in the cat spinal cord of control animals and animals treated with clonidine; and 2) to compare two routes of clonidine administration (intravenous or intrathecal) in order to determine which route elicits the most alterations in immunoreactive fiber density.
