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J R Naranjo

Publications and source records attributed to J R Naranjo.

At least 55 records · Page 3Linked to original sources
PubMed1989

Involvement of spinal monoaminergic pathways in antinociception produced by substance P and neurotensin in rodents.

The antinociceptive effects of substance P and of neurotensin have been determined in rodents after depletion of serotonin (5-HT) or noradrenaline (NA) in the spinal cord. The antinociceptive effect of substance P, given intraventricularly, in rats and mice was blocked after depletion of 5-HT in the spinal cord with the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) or with the inhibitor of the synthesis of 5-HT, p-chlorophenylalanine (PCPA), but not after depletion of NA in the spinal cord with the neurotoxin 6-hydroxydopamine (6-OHDA). Conversely, the antinociceptive effect of neurotensin in mice was blocked after lesion of spinal NA pathways with 6-OHDA. When 5-HT spinal pathways of mice were lesioned with 5,7-DHT, neurotensin-induced antinociception was blocked 7 but not 15 days after the lesion. p-Chlorophenylalanine failed to prevent this effect of neurotensin. The results suggest that the antinociceptive effect of substance P depends on the integrity of spinal 5-HT neurones, whereas that of neurotensin depends on spinal NA neurones and, only to a limited extent, on 5-HT neurones. It seems that different descending systems are involved in the antinociception elicited by these two neuropeptides.

5,7-Dihydroxytryptamine↗
PubMed1988

Differential activation of spinal cord dynorphin and enkephalin neurons during hyperalgesia: evidence using cDNA hybridization.

A unilateral experimental inflammation of the hindlimb produces hyperalgesia to both mechanical and radiant thermal stimuli that is rapid in onset. During this period, parameters of dynorphin biosynthesis are elevated to a much greater degree than those of the enkephalin system. An increase in the content of the peptide dynorphin A(1-8) occurs in the spinal cord segments that receive sensory input from the affected limb. This is accompanied by a rapid (within 24 h) and pronounced increase in the levels of mRNA coding for the dynorphin protein precursor. Maximum elevations (6- to 8-fold) of preprodynorphin mRNA are observed between days 2 and 5 subsequent to the induction of inflammation. Compared to the increase in mRNA, the increase in dynorphin A(1-8) peptide was appreciably delayed and proportionately less; maximal increases in peptide (3-fold) were seen at day 5 of inflammation. Dorsal spinal cord preproenkephalin mRNA is elevated to a lesser degree (50-80%). However, the increase in preproenkephalin mRNA is apparently not enough to yield a measurable increase in the proenkephalin-derived peptide met5-enkephalin-Arg6-Gly7-Leu8, the levels of which showed no significant change during the 14-day inflammatory period. These data suggest the active participation of opioid neurons, especially those containing dynorphin, at the spinal level, in the modulation of sensory afferent input during peripheral inflammatory pain states.

Animals↗
PubMed1988

Negative feedback regulation of the content of proenkephalin mRNA in chromaffin cell cultures.

The content of proenkephalin messenger RNA (PEmRNA) in cultured bovine adrenal chromaffin cells was reduced in the presence of reserpine (1 nM to 0.1 microM) with a return to basal levels 3 days after removal of the drug. In these cells, the basal release of Met5-enkephalin-Arg6-Phe7 immunoreactivity (MERF-IR) into the medium was significantly decreased when the cultures were pretreated with 0.2 microM reserpine for 3 days. The addition of 0.1 microM etorphine for 3 days also decreased the basal release of MERF-IR without depleting stores of catecholamines. Neither drug modified the total (cells + medium) amount of MERF-IR. In contrast, reserpine was without effect on levels of PEmRNA or release of Met5-enkephalin immunoreactivity (ME-IR) in primary cultures of the striatum of the fetal rat. The present data establish a correlation between inhibition of the secretion of enkephalin and reduced accumulation of its specific mRNA, suggesting a negative feedback inhibition by low molecular weight enkephalins.

Animals↗
PubMed1987

Hypotensive effect of naloxone on high blood pressure induced by stress in the rat.

A naloxone-reversible enhancement of systolic blood pressure (BP) was induced in rats by application of three different types of stressor, i.e. intense light and sound, cold and foot-shock. In the case of labile high BP provoked by short-term isolation, the opiate antagonist naloxone (1 mg/Kg, i.p.) was also found to reverse hypertension. Naltrexone (2.5 mg/Kg, i.p.) also diminished high BP readings of briefly isolated rats. Conversely, blockade of the opiate receptor with naloxone did not alter elevated BP in cases of established hypertension (spontaneously hypertensive rats, deoxycorticosterone (DOCA)-salt rats and long-term isolated rats). These data can be taken as an evidence of opioid involvement at the onset of high BP readings induced by stress. However, once hypertension becomes established, the opioid system appears to recover its silent features.

Acoustic Stimulation↗
PubMed1987

Analgesic dipeptide derivatives. 3. Synthesis and structure-activity relationships of o-nitrophenyl-modified analogues of the analgesic compound H-Lys-Trp(NPS)-OMe.

A series of analogues of the analgesic dipeptide derivative H-Lys-Trp(NPS)-OMe has been designed to determine the influence of the (2-nitrophenyl)sulfenyl (NPS) moiety on the activity. The syntheses and antinociceptive effects of these analogues of general formula H-Lys-Trp(R)-OMe [R = phenylsulfenyl (PS) (9); R = (2-carbomethyoxyphenyl)sulfenyl (CmPS) (10); R = (4-nitrophenyl)sulfenyl (pNPS) (11); R = (2,4-dinitrophenyl)sulfenyl (DNPS) (12); R = [2-(acetylamino)-2-carbomethoxyethyl]sulfenyl (AacCmES) (13); R = [2-(acetylamino)phenyl]sulfenyl (AacPS) (17); R = tert-butylsulfenyl (t-BuS) (23); R = (2-carbomethoxyethyl)sulfenyl (CmES) (24)] are described. Reaction of Z-Lys(Z)-Trp-OMe (3) with PS-, CmPS-, pNPS-, DNPS-, and AacCmES-Cl afforded the corresponding 2-(sulfenyl)tryptophan derivatives, which on treatment with boron-tris(trifluoroacetate)/trifluoroacetic acid or trimethylsilyl iodide in acetonitrile (Me3SiI/CH3CN) provided 9-13, respectively. Sulfenylation of 3 with NPS-Cl gave Z-Lys(Z)-Trp(NPS)-OMe, which, on catalytic hydrogenation of the nitro group using 10% Pd/C followed by acetylation of the resulting amino function and removal of the protecting Z groups, gave 17. Condensation of 2-(tert-butylsulfenyl)- and 2-[(2-carbomethoxyethyl)sulfenyl]tryptophan methyl ester, obtained by reaction of methyl 3a-hydroxy-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indole-2-carboxyla te with the corresponding thiol, with Z-Lys(Z)-OSu afforded Z-Lys(Z)-Trp(t-BuS)-OMe and Z-Lys(Z)-Trp(CmES)-OMe, which on treatment with Me3SiI/CH3CN provided 23 and 24, respectively. Intracerebroventricular administration of 10 elicited a naloxone-reversible antinociceptive effect in mice similar to that of H-Lys-Trp(NPS)-OMe. No analgesia was however found with the phenylsulfenyl or acyclic sulfenyl substituted dipeptides 9, 11, and 17 or 13, 23, and 24. The Trp(DNPS)-containing analogue was neurotoxic. Structure-activity studies indicate that the role of the NPS and CmPS moieties could be related to the adoption of a preferential active conformation.

Analgesics↗
PubMed1987

Proenkephalin gene expression in the PC12 pheochromocytoma cell line: stimulation by sodium butyrate.

The differentiation promoter sodium butyrate increases the content of Met5-enkephalin-Arg6-Gly7-Leu8 (Met5-enk-RGL)-immunoreactive peptides in PC12 pheochromocytoma cells, which, unlike mature adrenomedullary chromaffin cells, contain exceedingly low levels of opioid peptides. These butyrate-induced enkephalin-immunoreactive peptides, which are specific products of the proenkephalin gene, consist principally of two high mol wt forms of amino-terminally extended Met5-enk-RGL. These high mol wt peptides, with apparent mol wt of 20,000 and 10,000, are approximately the same size as the two major immunoreactive peptides found in adult New England Deaconess Hospital rat adrenal. The low mol wt Met5-enk-RGL-immunoreactive peptide found in butyrate-treated cells is similar in size to authentic Met5-enk-RGL, which is not found in the adrenal medulla of the adult rat. When PC12 cells are grown as a tumor in vivo, the amount of Met5-enk-RGL-immunoreactive peptide increased only slightly above the level found in control cells grown in vitro and consisted exclusively of the highest mol wt immunoreactive species. In PC12 cells, the butyrate-stimulated elevation in the content of Met5-enk-RGL-immunoreactive peptides may involve changes in transcription, since the peptide increase is preceded by a 2- to 3-fold increase in the level of proenkephalin mRNA. These results suggest that the PC12 cell line may be useful for investigating those factors that control the initial expression and processing of proenkephalin-derived peptides during embryogenesis.

Adrenal Gland Neoplasms↗
PubMed1987

Regulation of striatal enkephalin turnover in rats receiving antagonists of specific dopamine receptor subtypes.

The hypothesis that striatal dopamine regulates enkephalin (ENK) synthesis is supported by the increase of striatal proenkephalin mRNA and ENK after intranigral injection of 6-hydroxydopamine. In order to elucidate which dopamine receptor subtype is operative in the regulation of the dynamic state of ENK, the effect of drugs that block D-1 or D-2 receptor selectively was studied. Daily administration of 140 mumol/kg s.c. of the D-2 antagonist I-sulpiride twice daily for 2 weeks produces a 30% decrease in the content of striatal proenkephalin mRNA and ENK. In contrast, a 50% increase was observed after 2 weeks of treatment with the D-1 antagonist SCH 23390 at 74 nmol/kg s.c. three times a day. Hence, it can be inferred that the endogenous activation of D-1 tonically decreases striatal ENK synthesis. Removal of this neurally mediated regulation either by a specific pharmacologic blockage of D-1 or by lesioning with 6-hydroxydopamine increases the biosynthesis of ENK. The increase of ENK biosynthesis elicited by denervation with 6-hydroxydopamine cannot be due to the endogenous activation of D-2 receptors and must be due to the inactivation of the tonic inhibition exerted by D-1 receptors.

Animals↗
PubMed1986

Evidence for a central but not adrenal, opioid mediation in hypertension induced by brief isolation in the rat.

Naloxone was found to provoke a hypotensive effect related to the dose on high blood pressure (BP) induced by short-term isolation in young rats. Another opiate antagonist, nalorphine, also reduced the arterial pressure of socially deprived rats. In contrast, naltrexone methylbromide that selectively blocked peripheral opiate receptors did not alter the elevated BP. To investigate whether adrenomedullary opioids were somehow implicated in the development of isolation-induced hypertension, bilaterally adrenalectomized rats were kept under social deprivation for 7 consecutive days. The data obtained indicated that high systolic BP developed in the same manner as in intact rats run in parallel. In conclusion, central opioids appear to be involved in BP elevation due to the stress generated by brief social deprivation in young rats.

Adrenalectomy↗
PubMed1986

Kindling enhances the stimulation of inositol phospholipid hydrolysis elicited by ibotenic acid in rat hippocampal slices.

The increment of inositol phospholipid hydrolysis elicited by ibotenic acid (IBO) is greater in hippocampal slices prepared from brain of rats receiving single or repeated hippocampal electrical stimulation or electrically induced amygdala kindling. In the latter group of rats, a potentiation of IBO stimulation of inositol phospholipid hydrolysis was associated with stage 3-4 of kindling according to Racine's scale. This increment returned to normal within one month after withdrawal from electrical stimulations. In both control and stimulated animals, 2-amino-4-phosphonobutyric acid antagonized the increment of inositol phospholipid metabolism elicited by IBO. The stimulation of inositol phospholipid hydrolysis elicited by carbamylcholine and norepinephrine was virtually unaffected by amygdala kindling.

Amygdala↗
PubMed1986

Changes in the dynamic state of brain proenkephalin-derived peptides during amygdaloid kindling.

The dynamic state of the proenkephalin (PE) gene products during and after development of amygdaloid kindling was assayed by monitoring changes of the accumulation of PE mRNA and changes in proenkephalin-related peptides. A parallel determination of PE mRNA and peptides from the same sample was conducted in this study. Electrical stimulation of the amygdala causes early increases in the PE mRNA content in that structure and in the hippocampus. Other areas related with the amygdaloid complex do not exhibit such an early increase, but this alteration occurs when the kindling process is fully established. Enkephalin content increases early in amygdala and hippocampus presumably owing to an increase in synthesis rate. Also, the enkephalin content of areas connected with amygdala and hippocampus such as the entorhinal cortex, the nucleus accumbens, and the frontal and occipital cortex exhibits an increase. A clear tendency towards normalization is observed after a recovery period of 2-3 months. Rekindling of the animals after this recovery period does not elicit a similar pattern of changes in the dynamic state of enkephalin system, even though the animals rekindle with just one single stimulation. The present data suggest that the enkephalinergic neurons participate in the development and spreading of kindling phenomena after amygdaloid stimulation, but they do not seem to play any role in mediating maintenance of the kindling state.

Amygdala↗
PubMed1986

Permissive effect of dexamethasone on the increase of proenkephalin mRNA induced by depolarization of chromaffin cells.

In cultured bovine chromaffin cells, changes in the dynamic state of enkephalin stores elicited experimentally were studied by measuring cellular proenkephalin mRNA, as well as enkephalin precursors and authentic enkephalin content of cells and culture media. In parallel, tyrosine hydroxylase mRNA and catecholamine cell content were also determined. Low concentrations (0.5-100 pM) of dexamethasone increased the cell contents of proenkephalin mRNA and enkephalin-containing peptides. High concentrations of the hormone (1 microM) were required to increase the cell contents of tyrosine hydroxylase mRNA and catecholamines. Depolarization of the cells with 10 microM veratridine resulted in a depletion of enkephalin and catecholamine stores after 24 hr. The enkephalin, but not the catecholamine, content was restored by 48 hr. An increase in proenkephalin mRNA content might account for the recovery; this increase was curtailed by tetrodotoxin and enhanced by 10 pM dexamethasone. Tyrosine hydroxylase mRNA content was not significantly modified by depolarization, even in the presence of 1 microM dexamethasone. Aldosterone, progesterone, testosterone, or estradiol (1 microM) failed to change proenkephalin mRNA. Hence, dexamethasone appears to exert a specific permissive action on the stimulation of the proenkephalin gene elicited by depolarization. Though the catecholamines and enkephalins are localized in the same chromaffin granules and are coreleased by depolarization, the genes coding for the processes that are rate limiting in the production of these neuromodulators can be differentially regulated.

Adrenal Medulla↗
PubMed1986

Increased spinal cord dynorphin mRNA during peripheral inflammation.

Injection of a complete Freunds adjuvant-saline emulsion into the hindpaw of the rat induces a peripheral inflammatory process accompanied by pronounced increase (3 fold) in spinal cord dynorphin content. A marked increase (approximately 9 fold) in the mRNA coding for the preprodynorphin precursor accompanies the increase in peptide. The parallel elevations of the mRNA and peptide product suggest that an increased activity of dynorphin neurons occurs in spinal cord in response to altered afferent input due to the peripheral inflammatory process.

Animals↗
PubMed1985

Association between hypoalgesia and hypertension in rats after short-term isolation.

By isolating young rats (90-100 g) a state of hypertension and tachycardia was induced after 7 days or a longer period of social deprivation. Clonidine, a drug used to treat hypertension in man, readily reversed the high blood pressure and heart rate in this experimental model of hypertension. In two different tests, an elevated nociceptive threshold was shown to be present in isolated animals as compared to group-housed rats. Naloxone was found to reverse this hypoalgesic state. The opiate antagonist also diminished the high blood pressure in the socially-deprived animals. Moreover, after 7 days of isolation, 24 hr of housing the rats in groups of five made the level of blood pressure and the sensitivity to pain return to control values. In this experimental model, in which hypertension was linked to stressful housing conditions, the data suggest that high blood pressure and hypoalgesia are closely associated.

Animals↗
PubMed1985

Beta-endorphin: a common factor in the antihypertensive action of clonidine-type imidazolines in spontaneously hypertensive rats.

The hypotensive action of two novel imidazolinic alpha-adrenergic agonists (ICI-106270 and UK-14304) with similar pharmacological properties to clonidine was shown in spontaneously hypertensive (SH) rats. The antihypertensive effect of the clonidine-type agents was prevented by either peripheral administration of the opiate antagonist naloxone or by intracerebroventricular (i.c.v.) injection with a specific antibody against human beta-endorphin (BEN). A dose-response relationship was found for the hypotensive effect of i.c.v. given BEN in SH rats, the low blood pressure being significantly reversed by further treatment with either naloxone or anti-beta h-endorphin. These data confirm and extend the notion of a BEN mediation in the antihypertensive action of clonidine-type alpha-adrenergic agonists in SH rats.

Animals↗
PubMed1985

Synthesis and analgesic properties of N-phosphorylated derivatives of Phe-Ala and Phe-Gly.

N-Phosphoryl dipeptides derived from Phe-Ala, Phe-Ala-NH2 and Phe-Gly-NH2 were synthesized and their analgesic activity was evaluated in mice. Intracerebroventricular administration of P-Phe-Ala-NH2 produced a 100-fold increase in the analgesic potency of Phe-Ala and led to a potentiation and prolongation of the analgesic effect of the exogenously administered Met-enkephalin.

Alanine↗
PubMed1984

Analgesic activity of substance P in rats: tolerance and cross-tolerance with enkephalin.

In rats, tolerance to the analgesic effect of intraventricular substance P (SP) develops quickly. In rats made tolerant to [D-Ala2, D-Leu5]enkephalin the analgesic efficacy of SP is reduced significantly. The latter result suggests some overlap in the sites of action of SP and [D-Ala2,D-Leu5] enkephalin. Since SP seems to lack any direct effect on opiate receptors of the brain, the present data suggest that the analgesic effect of SP is mediated by enkephalin release at supraspinal levels which are related to pain control.

Analgesics↗
PubMed1984

Locomotor activation induced in rodent by substance P and analogues. Blockade of the effect of substance P by met-enkephalin antiserum.

Intraventricular administration of substance P (SP), of the heptapeptide SP5-11 and of DiMe-C7, a stable analogue of SP5-11 induced locomotor activation in rats and in mice. The activating effect of substance P was longer-lasting in mice than in rats, whereas the effect of the two heptapeptides appears to be more marked in rats than in mice. The locomotor stimulation induced by substance P was blocked by naloxone and by the specific antiserum against met-enkephalin, suggesting that this effect is possibly mediated by released of this opioid peptide. Since the activating effect of substance P was also blocked by haloperidol, it is proposed that substance P produces behavioural excitation by activating dopaminergic systems, implicated in the control of locomotion, through interposed enkephalinergic neurones.

Animals↗