Mapping, in the rat central nervous system, of morphine‐induced changes in turnover of 5‐hydroxytryptamine.

Abstract

SUMMARY1. It is known that the full clinical effect of morphine is not seen if those neurones of the central nervous system which contain 5-hydroxytryptamine (5-HT) have been inactivated. Morphine increases 5-HT turnover in brain and cord, and the present work is an attempt at mapping the sites at which turnover is accelerated.2. The degree of interaction at various sites of the C.N.S. was measured by the increment in the content of 5-hydroxyindol-3-yl acetic acid (5-HIAA) elicited by morphine in rats pre-treated with probenecid. The effect was produced by as little as 3-5 mg morphine hydrochloride/kg; for the sake of convenience this dose was doubled in most experiments. Pre-treatment with probenecid was not necessary for the effect, but a minimum interval of 90 min between injection of morphine and analysis of the brain was essential.3. Morphine did not act indiscriminately on all 5-HT neurones, as seen by the fact that the increment in 5-HIAA formation was independent of the density of 5-HT neurones in the tissue. Nor was there any relation between basal 5-HT turnover of a region and the size of its response to morphine.4. Highly reactive sites were found in dorsal cord, medulla, superior colliculi, substantia nigra, thalamus, hypothalamus, amygdala and striatum. Cortical areas were less responsive, but with large differences among themselves. Hippocampus, central grey, olfactory bulb, cerebellum and white matter had lower or negligible increases in 5-HT turnover. There was no increase in the turnover of the (non-neural) 5-HT of the pineal gland.5. The relation of the reactive sites to their content in endogenous opioids and to the probable localization of the pharmacological actions of morphine is discussed.

GABAergic and Glutamatergic Afferents in the Dorsal Raphe Nucleus Mediate Morphine-Induced Increases in Serotonin Efflux in the Rat Central Nervous System

“…This confirms reports that opioids increase 5-HT turnover and efflux in the DRN and forebrain regions innervated by the DRN (Snelgar and Vogt, 1981;Spampinato et al, 1985;Grauer et al, 1992;Tao and Auerbach, 1995). Increased 5-HT efflux was mediated at least in part by opioid receptors on GABAergic neurons in the DRN.…”

Effects of Opiate Antagonists on Serotonin Turnover and on Luteinizing Hormone and Prolactin Secretion in Estrogen- or Morphine-Treated Rats

“…For example, prior reduction of brain 5-HT with p-cholorophenylalanine [18] or 5,7-dihydroxytryptamine [19] blunts morphine's elevation of PRL, suggesting that morphine releases 5-HT. Moreover, admin istration of (3-endorphin or morphine acutely elevates 5-HT turnover in whole hypothalamus [29,33]. The present find ing that morphine increases medial preoptic 5-HT turnover suggests that this region is a major site of opiate-5-HT interaction.…”

“…Met-enkephalin and |Tendorphin appear responsive to estradiol treatment [6,13,37], and opiate alkaloids and peptides mimic the acute stimulation of PRL and depression of LH by estradiol [17,35]. Morphine stimulates 5-HT turnover in gross brain dissections [29]. Moreover, morphine's neuroen docrine effects are prevented by disruption of serotonergic neurotransmission [14.…”

Central GABA‐ergic systems and analgesia

“…GABA-ergic mechanisms might also be connected with opiate, ethanol, and barbiturate actions and tolerance in various vertebrates, including man [see, e.g., Barker and McBurney, 1979;Mandel and DeFeudis, 1979;DeFeudis and Orensanz-MuBoz, 1980;DeFeudis and Mandel, 1981;Krogsgaard-Larsen, 19811. Regarding the actions of opiate analgesics (e.g., morphine) and their antagonists (e.g., naloxone, nalorphine), it should be recalled that several neurotransmitters other than GABA have been implicated (e.g., acetylcholine (ACh), norepinephrine (NE), dopamine (DA), S-hydroxytryptamine (5-HT); see, e.g. [Johanneson, 1967;Harris, 1970;Sparkes and Spencer, 1971;Pollard et al, 1977;Sugrue, 1979;Yaksh, 1979;Brase, 1979;Snelgar and Vogt, 1981;Fan et al, 1981;Mennini et al, 1981;Seltzer et a]., 19811). Also, with the discovery of the endogenous opioid peptides (e.g., enkephalins, endorphins; see, e.g.…”