Influence of various combinations of specific antibody dose and affinity on tissue imipramine redistribution.

1. This study was designed to evaluate the distribution kinetics of imipramine (Imip) in the brain and the main peripheral organs (heart, kidney, liver and lung) of rats, and to establish the relationship between the redistribution of Imip from these tissues and the immunoreactive capacity (dose and affinity) of anti-TCA IgG. 2. [3H]-Imip (1 nmol kg(-1) body weight) was injected intravenously 6 min before the i.v. injection of antibodies. At this time, the concentrations of Imip and its main metabolites in plasma were determined. The radioactivity measured corresponded to 91.7% Imip, indicating that the pharmacokinetics reflected essentially Imip. Plasma and tissue Imip contents were measured over the interval 1 to 90 min in control and in treated rats. The antibodies used were a murine monoclonal IgG1 (Ka=3.8 10(7) M(-1)) at an IgG1/Imip molar ratio of 1000 (IgG1 1000), and a sheep polyclonal IgG (TAb, Ka=1.3 10(10) M(-1)) at IgG/ Imip molar ratios of 1, 10 and 100 (TAb1, TAb10 and TAb100). 3. The anti-TCA IgG increased the plasma [3H]-Imip concentrations: the AUC1-->60 min for [3H]-Imip were 4 (IgG1 1000), 9 (TAb1), 33.9 (TAb10) and 41.4 (TAb100) times higher in the treated groups than in the controls. The opposite effect occurred in the brain, heart and lungs, with large, rapid decreases in Imip. The increase in plasma Imip and the decrease in tissue Imip depended on the immunoreactive capacity (NKa) of the antibody, where N=molar concentration of IgG binding sites and Ka=IgG affinity constant. Maximal plasma and tissue redistribution occurred when NKa=33.8 x 10(4). 4. Imip redistribution can be controlled using various doses or affinities of specific antibodies, and the resulting rapid, extensive Imip redistribution from the main target organs could be very promising for TCA detoxification.

Redistribution of imipramine from regions of the brain under the influence of circulating specific antibodies.

The kinetics of brain-to-blood redistribution of imipramine (IMI) was assessed in nine brain regions of control rats and rats given anti-tricyclic antidepressant (anti-TCA) antibody. Two antibodies were given intravenously 6 min after intravenous [3H]IMI (1 nmol/kg). One was a murine monoclonal IgG1 (Ka = 3.8 x 10(7) M(-1)) at an IgG/IMI molar ratio of 1,000 (IgG1,000), and the other was a sheep polyclonal IgG (TAb; Ka = 1.3 x 10(10) M(-1)) at IgG/IMI molar ratios of 1, 10, and 100 (TAb1, TAb10, and TAb100). In the control rats, IMI was rapidly taken up by the brain (Cmax at 5 min) with no significant differences among the brain regions (4.1 +/- 0.4 to 5.4 +/- 0.6 pmol/ g), and brain IMI then declined monoexponentially with a half-life of 44.2 min (cerebellum) to 77.3 min (hippocampus). The greatest IMI content was in the frontal cortex and the lowest in the cerebellum. The antibodies (except TAb1) stimulated the extent and rate of IMI redistribution from all the brain regions depending on the immunoreactive capacity (NKa) of the antibody. The antibody with the highest NKa (TAb100) had the greatest effect. The fraction of IMI removed from the brain was 58-74%, and the redistribution half-life was 7.9-15.6 min; the mean residence time was reduced by 66-75% (11.8-23.9 min). These results demonstrate that circulating anti-TCA IgG rapidly and reliably removes IMI from the brain, indicating that immunotoxicotherapy could be an efficient procedure for accelerating the removal of TCA from the brain.

Facilitation of imipramine efflux from the brain by systemic specific antibodies.

1. This study investigated the capacity of circulating anti-tricyclic antidepressant (TCA) IgG to increase the efflux of imipramine (Imip) from the rat brain. 2. A tracer amount of [3H]-Imip (40 pmol) was injected into the cerebral lateral ventricle and its efflux was determined in control rats and in rats given anti-TCA antibody. The monoclonal anti-TCA IgG1 was injected i.v. 48 h before Imip at 4 IgG:Imip molar ratios (10, 100, 1000 and 10,000). The [3H]-Imip in arterial and venous plasma was measured for up to 60 min, and in the brain and peripheral organs (heart, liver, lung, kidney) 5 and 60 min after Imip injection. 3. The arterial plasma concentration of Imip in control rats was significantly higher (26.7 +/- 2.1 pM) than the venous one (17.7 +/- 2.0 pM) at 5 min, indicating that Imip released from brain becomes distributed in peripheral tissues. These concentrations were not significantly different at 60 min suggesting that Imip was, at this time, redistributing from extravascular tissues to the blood. In rats given anti-TCA IgG, any Imip leaving the brain was immediately bound by the circulating antibody at 5 min. This greatly reduced the Imip in the heart (63.9%) and lung (61.3%) at the highest IgG:Imip ratio. The brain Imip was markedly lower at 60 min (31.5% with an IgG Imip ratio of 1000 and 57.5% at a ratio of 10,000). The two lowest IgG:Imip ratios had less effect on the plasma Imip because of the relative low affinity of the anti-TCA IgG (3.8 x 10(7) M-1). 4. These data indicate that the anti-TCA IgG facilitated the efflux of Imip from the brain, even though these antibodies cannot cross the blood-brain barrier. This may be an efficient system for increasing drug organ clearance, as more than half the Imip in the brain was actively removed by the antibody in 1 h.

Dose-dependent delivery of colchicine to the rat hippocampus by microdialysis.

The time courses of the colchicine delivery and diffusion rate in the brain were studied by microdialysis in the rat. Microdialysis allowed the exposure of the brain tissue to colchicine to be regulated, unlike a bolus injection. Colchicine was infused directly into the dorsal hippocampus at 40 ng/ml and 40 micrograms/ml, for 8 h. The amount of colchicine delivered to the brain and the diffusion rate from the probe were dose-dependent: colchicine diffusion into the brain was linear at 40 ng/ml but tended to plateau after 4 h at 40 micrograms/ml. The drug actually delivered with the higher dosage was only about 50% of that predicted from a constant diffusion. The total amount delivered at 40 ng/ml was 3.73 +/- 0.14 ng and at 40 micrograms/ml, it was 2.06 +/- 0.20 micrograms. Thus tissues surrounding the infusion site were saturated at high concentration and no more colchicine was diffused. Postmortem measurements of colchicine concentration in the forebrain confirmed these findings. Hence, the way in which colchicine is delivered to the brain is a critical factor for induction of its neurotoxic effects. These data open the way to a research on the correlation between local brain concentrations of colchicine and neurodegenerescence.

Brain microdialysis in the mouse.

Microdialysis of small brain areas of OF1 mice is shown to be feasible using the smallest commercially available probes (CMA/11). The brain areas studied were the dorsal hippocampus and nucleus accumbens. The basal concentrations of biogenic amine metabolites in dialysate samples were measured by HPLC with electrochemical detection (ED). The basal levels of MHPG, DOPAC, and HVA in the dorsal hippocampus were obtained immediately after probe insertion, whereas the basal 5-HIAA concentration gradually declined. The stable levels of DOPAC, HVA, and 5-HIAA in the nucleus accumbens were reached in 80 min. Histological controls showed the tract of the dialysis membrane within the studied sites. This procedure could allow simultaneous correlation of the neurobiochemical changes and pharmacological responses, and could facilitate further biochemical and pharmacokinetic research in the mouse.

Involvement of hydroxylated metabolites in amphetamine-induced hypothermia in mice.

1. The hydroxylated metabolites of amphetamine, p-hydroxyamphetamine (p-OHA) and p-hydroxynorephedrine (p-OHN), were administered intracerebroventricularly in mice in order to evaluate their ability to elicit hypothermia. 2. Intracerebroventricular (i.c.v.) administration of p-OHA and p-OHN (1, 3 and 9 micrograms/mouse) induced maximal hypothermia 30 min after injection. p-OHA and p-OHN (9 micrograms, i.c.v.) produced maximal decreases in rectal temperature of -6.48 +/- 0.44 degrees C and -3.82 +/- 0.42 degrees C, respectively. Both metabolites are more effective than amphetamine (at 9 micrograms, i.c.v., -3.32 +/- 0.75 degrees C). 3. Pretreatment with haloperidol (5 micrograms, i.c.v.) suppressed the fall in temperature produced by p-OHA (3 micrograms, i.c.v.) and reduced that produced by p-OHN (3 micrograms, i.c.v.), respectively. The selective dopaminergic D1 receptor antagonist, SCH 23390, and the D2 receptor antagonists, sultopride and metoclopramide, were without effect on the hypothermia induced by either metabolite. Similarly, amphetamine-induced hypothermia was only inhibited by haloperidol. Apomorphine (0.1 mg kg-1, i.p.) did not potentiate the hypothermia induced by either metabolite, whereas the selective dopaminergic D2 agonist, quinpirole (0.2 mg kg-1, i.p.) did. Amphetamine-induced hypothermia was potentiated by apomorphine and quinpirole. 4. Neither the 5-hydroxytryptamine (5-HT) receptor blocker, cyproheptadine, nor the 5-HT receptor agonist, quipazine, modified metabolite-induced hypothermia. In contrast, amphetamine-induced hypothermia was affected by these 5-HT drugs. 5. The neuropeptide CCK-8 (0.04 mg kg-1, i.p.) and gamma-butyrolactone (40 mg kg-1, i.p.) potentiated the hypothermia produced by amphetamine and its metabolites. Conversely, desipramine (20 mg kg-1, i.p.) antagonized it.(ABSTRACT TRUNCATED AT 250 WORDS)

Facilitation of amphetamine-induced hypothermia in mice by GABA agonists and CCK-8.

1. Amphetamine-induced hypothermia in mice is facilitated by dopaminergic stimulation and 5-hydroxytryptaminergic inhibition. The present study was designed to investigate: (a) the involvement of other neuronal systems, such as the gamma-aminobutyric acid (GABA), the opioid and the cholecystokinin (CCK-8) systems; (b) the possible contribution of hydroxylated metabolites of amphetamine to the hypothermia; (c) the capacity of dopamine itself to induce hypothermia and its mechanisms, in order to clarify the resistance of amphetamine-induced hypothermia to certain neuroleptics. 2. Pretreatment with the GABA antagonists, bicuculline and picrotoxin, did not inhibit amphetamine-induced hypothermia. The GABAB agonist, baclofen (2.5 mg kg-1, i.p.) potentiated this hypothermia, whereas the GABAA agonist, muscimol, did not. gamma-Butyrolactone (GBL) (40 mg kg-1, i.p.) and the neuropeptide CCK-8 (0.04 mg kg-1, i.p.) also induced potentiation. The opioid antagonist, naloxone, was without effect. 3. Dopamine itself (3, 9, 16 and 27 micrograms, i.c.v.) induced less hypothermia than the same doses of amphetamine. Sulpiride did not block dopamine-induced hypothermia, but pimozide (4 mg kg-1, i.p.), cis(z)flupentixol (0.25 mg kg-1, i.p.) and haloperidol (5 micrograms, i.c.v.) did. The direct dopamine receptor agonist, apomorphine, did not alter the hypothermia. Neither the 5-hydroxytryptamine (5-HT) receptor blocker, cyproheptadine, nor the inhibitor of 5-HT synthesis, p-chlorophenylalanine (PCPA), modified dopamine-induced hypothermia. Fluoxetine, an inhibitor of 5-HT reuptake, had no effect, whereas quipazine (6 mg kg-1, i.p.), a 5-HT agonist, totally prevented the hypothermia. Hypothermia was unaffected by pretreatment with CCK-8. 4. These data indicate that the hypothermia induced by amphetamine involves not only dopaminergic and 5-hydroxytryptaminergic systems which are functionally antagonistic, but is also facilitated by direct or indirect GABA and CCK-8 receptor stimulation. This facilitation could result, in part, from modulation of dopaminergic neurotransmission. This may explain the apparent resistance of amphetamineinduced hypothermia to some neuroleptics, while dopamine-induced hypothermia is not resistant. The possible action of hydroxylated metabolites of amphetamine may also help to explain these differences.

Opioid involvement in TRH-induced antinociception in the rat following intracerebral administration.

Thyrotropin-releasing hormone (TRH) has an antinociceptive action in the rat. Antinociception was observed using a thermal stimulus (tail-flick test) after TRH administration into lateral ventricle, nucleus raphe magnus, nucleus reticularis paragigantocellularis and amygdaloid nuclei. This effect was short-lived since it was completely abolished 60 min after intracerebroventricular administration. TRH may interact with the opioid systems as its antinociceptive effect was blocked by pretreatment with naloxone.

Potentiation by TRH of the effect of antidepressants in the forced-swimming test, involvement of dopaminergic and opioid systems.

1. It has been shown that thyrotropin releasing hormone (TRH) can potentiate the effects of the antidepressant, imipramine, as measured by the mouse forced-swimming test. This potentiation is not associated with an increase of effective levels of noradrenaline in the synaptic clefts, but depends upon the integrity of opioid systems. The present study was designed to investigate: (a) the potentiation by TRH of the effects of other antidepressants, using the same test; (b) the possible involvement of other neuronal systems, such as the 5-hydroxytryptaminergic and dopaminergic systems; (c) the contribution of the opioid and dopaminergic systems to the potentiation of the actions of other antidepressants by TRH. 2. The effects of nortriptyline, amineptine, maprotiline, nomifensine and mianserin, but not that of clomipramine, were potentiated by TRH (2 mg kg-1, i.p.). The inhibitor of 5-hydroxytryptamine synthesis, p-chlorophenylalanine (PCPA), did not prevent the effect induced by imipramine plus TRH. Blockade of dopaminergic systems by gamma-butyrolactone (GBL) (37.5 mg kg-1, i.p.), alpha-methyl-p-tyrosine (AMPT) (125 mg kg-1, i.p.) and apomorphine (0.025 mg kg-1, i.p.) antagonized the effects induced by various antidepressants alone (at high, effective doses) or at lower ineffective doses in association with TRH. The effect induced by imipramine plus TRH was also blocked by sulpiride (16 mg kg-1, i.p.). Pretreatment with the opioid antagonist, naloxone, inhibited the effects induced by nomifensine plus TRH or mianserin plus TRH but not those induced by nortriptyline plus TRH, maprotiline plus TRH or amineptine plus TRH. When high active doses of the antidepressants were used alone, only the clomipramine effect was blocked by naloxone. 3. These data indicate that TRH is able to potentiate the effect not only of imipramine but of other antidepressants in the mouse forced-swimming test, although these other antidepressants act in various ways on cerebral amines. The antagonism of the effects induced by the antidepressants alone or in association with TRH after blockade of dopaminergic systems may indicate a reversal of the effect of the antidepressants by blockade of dopaminergic systems. Hence, the same mechanisms would be involved in the effects induced by antidepressants alone or in association with TRH, with respect to dopaminergic systems. However, different mechanisms of action seem to be responsible for the potentiation of TRH of the effect of the various antidepressants, since the involvement of the opioid systems varies according to the antidepressant tested.

Predominant cytosolic distribution of serotonin in rat pineal gland in contrast to biogenic monoamine localization in midbrain and adrenal gland.

The subcellular distribution of serotonin and norepinephrine in the rat pineal gland was studied by tissue fractionation and compared with that of biogenic monoamines in the adrenal gland and midbrain. Homogenized tissues were fractionated by ultracentrifugation or by filtration through cellulose ester membranes. Most of the epinephrine (70-80%) and norepinephrine (62-82%) present in the adrenal glands was detected in the particulate fraction. The same distribution was found for serotonin (68.5%) and norepinephrine (59%) in the midbrain and for norepinephrine (62.5%) in the pineal gland. However, most of the serotonin in the pineal was found in the soluble fraction (89.5-98%). This suggests that the great majority of serotonin in the rat pinealocytes is cytosolic and thus is not stored in subcellular vesicles, in contrast to the biogenic monoamines in the midbrain or adrenal gland.

Changes in tuberoinfundibular dopaminergic neuron activity during the rat estrous cycle in relation to the prolactin surge: alteration by a mammary carcinogen.

An attempt was made to correlate the physiological or the dimethylbenz(a)anthracene (DMBA)-enhanced serum prolactin (PRL) surge, which occurs in the afternoon of proestrus in female Sprague-Dawley (SD) rats, with physiological or pathological changes in two biochemical estimates of the tuberoinfundibular dopaminergic (TIDA) neuron activity. Dopamine (DA) and dihydroxyphenylacetic acid (DOPAC) concentrations as well as tyrosine hydroxylase (TH) activity were measured in the median eminence (ME) of control or DMBA-pretreated SD rats throughout the estrous cycle in relation to PRL secretion. In both groups of females, while the DA content was fairly constant, the DOPAC content and TH activity in the ME fluctuated markedly throughout the estrous cycle. Thus, in control animals, the DOPAC content, DOPAC/DA ratio and TH activity which were stable on the days of diestrus and morning of proestrus were markedly decreased at noon and early afternoon when serum PRL levels began to rise. Later in the afternoon of proestrus, when serum PRL levels were maximal, there was a marked but transient increase in the DOPAC content and DOPAC/DA ratio as well as a brief surge in TH activity. In the evening of the same day, when serum PRL returned to basal levels, the DOPAC content, DOPAC/DA ratio and TH activity were low. Finally on estrus morning, the DOPAC content, DOPAC/DA ratio and TH activity increased again to reach the diestrus levels. In DMBA-pretreated females, similar fluctuations in TIDA neuronal activity occurred during the estrous cycle, but the dynamics of these changes was altered: the DOPAC/DA ratio and TH activity first showed a marked increase in the morning of proestrus day, before decreasing dramatically.(ABSTRACT TRUNCATED AT 250 WORDS)

Neuroleptic-induced hypothermia in mice: lack of evidence for a central mechanism.

The present study investigated the ability of neuroleptic drugs to induce hypothermia in mice when they were administered intraperitoneally (i.p.) or intracerebroventricularly (i.c.v.). Twelve neuroleptics belonging to five chemical classes including phenothiazines, butyrophenones, benzamides, thioxanthenes and diphenylbutylpiperidines were injected i.p. All of them, except benzamides, induced a dose-dependent decrease in rectal temperature. Neuroleptics were administered i.c.v. via cannulae previously implanted in mice to determine whether this response might have a central origin. None of the drugs tested induced hypothermia at doses which did not produce toxic effects. These negative results suggest that neuroleptics act to elicit hypothermia via a peripheral, rather than a central mechanism. Since some neuroleptics possess alpha-adrenolytic properties which could induce hypothermia by promoting vasodilatation, we attempted to antagonize the hypothermia produced by peripheral administration of two neuroleptics with phenylephrine, an alpha-adrenoceptor agonist that does not cross the blood-brain barrier. The hypothermia induced by both chlorpromazine and haloperidol was attenuated by phenylephrine, supporting the view that peripheral alpha-adrenoceptors may mediate neuroleptic-induced hypothermia.

TRH-induced antinociception: interaction with the opioid systems?

Mice were chronically treated with morphine or ethylketocyclazocine in order to induce a marked tolerance to their antinociceptive effect in the phenyl-p-benzoquinone writhing test. TRH (2 mg kg-1 i.p.) significantly reduced the number of writhes in non-tolerant mice, but did not alter the response of morphine- or ethylketocyclazocine-tolerant mice. TRH did not modify the binding of [3H]naloxone in mouse brain either in vitro (TRH: 10(-10)-10(-4) M) or ex vivo (TRH: 1-40 mg kg-1 i.p.). There was no dose-dependent modification of the in vivo binding of [3H]lofentanil in any of the mouse brain areas studied after TRH (1-40 mg kg-1 i.p.).

The regionalization of [3H]dihydrotetrabenazine binding sites in the mouse brain and its relationship to the distribution of monoamines and their metabolites.

[3H]Dihydrotetrabenazine binding was measured in 8 areas of the mouse brain. In all areas, binding occurred on a homogeneous class of sites (Kd approximately equal to 2.6 nM). The density of [3H]dihydrotetrabenazine binding sites strongly varied between the different brain structures; it was compared to endogenous levels of biogenic monoamines and their metabolites: the density is independent of the nature of the monoamine and of neuronal activity, but is highly correlated to the total amount of monoamines present in each structure.

Potentiation by TRH of the effect of imipramine on the forced-swimming test.

Discovery of the potentiation of thyrotropin releasing hormone (TRH)-induced hyperthermia in mice by antidepressants which activate alpha-adrenergic systems instigated investigation of other relations between TRH and antidepressants. For this study the forced-swimming test using mice was chosen since this test is more sensitive for selection of antidepressants which modify catecholaminergic systems than for those affecting 5-hydroxytryptaminergic systems. The effects of imipramine were potentiated by TRH. The involvement of alpha-adrenergic systems was then investigated in this effect since it is already known that these systems are directly implicated in the potentiation of TRH-induced hyperthermia by some antidepressants. Then the involvement of opiate systems was investigated since endogenous opiates are implicated in the action of some antidepressants, and some interactions between TRH and opiate systems are known to exist. TRH made effective a completely inactive dose of imipramine as small as 2 mg kg-1 (i.p.) or 1 microgram per mouse (i.c.v.). Pretreatment by both alpha 1- and alpha 2-adrenoceptor antagonists (phenoxybenzamine, 8 mg kg-1 i.p.; phentolamine, 4 mg kg-1 i.p.) or by a alpha 1-adrenoceptor antagonist (prazosin, 2 mg kg-1 i.p.) did not prevent this potentiation. In contrast the alpha 2-adrenoceptor antagonist (Yohimbine, 2 mg kg-1 i.p.) blocked the TRH effect. The imipramine potentiation by TRH was blocked by pretreatment with an opiate antagonist (naloxone, 1 mg kg-1 i.p.) and the potentiation was decreased in morphine-tolerant mice. 5 These data indicate that potentiation of the effects of imipramine on the forced-swimming test does not seem to be associated with an increase of effective levels of noradrenaline in the synaptic clefts and suggest an interaction between TRH and the opiate systems.

Effects of pGlu-His-Pro-amphetamine (TRH-amphetamine) on the isolated duodenum of the guinea-pig: antagonistic effect of amphetamine on TRH response.

pGlu-His-Pro-dexamphetamine (TRH-A) produced a contraction through the release of acetylcholine from postganglionic cholinergic neurons in the duodenum of the guinea-pig in the same manner as TRH. However, the affinity of TRH-A (pD2, 4.70) toward isolated duodenum was one thousandth that of TRH (pD2, 7.74). The effects of TRH-A (10(-4)M) were abolished by 10(-7) M TRH, but only partially (about 50%) inhibited by 10(-4) M d-amphetamine. D-Amphetamine showed no stimulatory effect on the myenteric nerves. However, the duodenal response to TRH (10(-6) M) was dose dependently inhibited by d-amphetamine (10(-6), 10(-5), 10(-4) M) while the phasic and tonic contractions caused by high K+ (40 mM) or the contractile responses to acetylcholine (10(-7) M) were not blocked by d-amphetamine. These results indicate that d-amphetamine may act as an antagonist to TRH without influencing the movement of calcium ions in smooth muscle or muscarinic receptors and that contractile responses to TRH-A are mediated through TRH receptors in the myenteric cholinergic nerves.

Iodoamphetamine as a new tracer for local cerebral blood flow in the rat: comparison with isopropyliodoamphetamine.

Rats were injected with iodoamphetamine synthesized and labeled with 125I or with 125I- isopropyliodoamphetamine , a molecule of established value for the determination of local cerebral blood flow. The blood kinetics, tissue distribution, and brain uptake index for each tracer exhibited practically no differences. Autoradiographic quantification of the local cerebral blood flow, calculated according to the microsphere model, produced identical results for both molecules. However, compared with the values reported for other tracers, our values constituted an underestimation of white matter blood flow and a more real estimation of hippocampal flow. It is concluded from the brain uptake of the derivatives of both amphetamines during the first minutes following their injection that these tracers can be used as a chemical microembolus for the measurement of local cerebral blood flow.

Thyrotropin releasing hormone-induced hyperthermia in mice: possible involvement of adrenal and pituitary glands.

To investigate the hyperthermic effect of thyrotropin releasing hormone (TRH) and its potentiation by exogenous catecholamines (CA), the role of the adrenal medulla and of the pituitary gland was studied in unoperated, adrenal-demedullated or hypophysectomized mice. In unoperated mice, TRH 40 mg kg-1 i.p. produced a hyperthermia which was accompanied by an increase in plasma noradrenaline (NA) and adrenaline (Ad). NA or Ad, both at a dose of 1 mg kg-1 i.p., enhanced the TRH-induced hyperthermia. Adrenal demedullation suppressed the hyperthermia and the increase of plasma CA produced by TRH but not the potentiation of this hyperthermia by exogenous CA. Hypophysectomy abolished the TRH-induced hyperthermia but not the increase of plasma CA or the potentiation of this hyperthermia by exogenous CA. These results suggest that, in mice, both the adrenal medulla and the pituitary gland play an essential role in TRH-induced hyperthermia but not in its potentiation.

Antinociceptive properties of thyrotropin releasing hormone in mice: comparison with morphine.

1 To investigate the antinociceptive activity of thyrotropin releasing hormone (TRH) in mice, different nociceptive stimuli were used. TRH (i.p.) was active in the phenyl-p-benzoquinone or acetic acid-induced writhing tests (chemical stimuli) and in Haffner's test (mechanical stimulus); its action decreased rapidly 15 min after intraperitoneal injection. 2 To determine whether the activity of TRH has a peripheral or central origin, we administered TRH intracerebroventricularly via cannulae previously implanted in mice. The results provide evidence that a central mechanism is involved in the analgesic effect of TRH since when given intracerebroventricularly it was 10,000 and 1,000 times more active against chemical and mechanical stimuli respectively than intraperitoneally. The action of TRH decreased rapidly 5 min after i.c.v. injection. Morphine was studied in these tests and it was found that at the peak effect TRH analgesia (i.c.v.) was greater than that of morphine (i.c.v.) on a molar basis. 3 To investigate the mechanisms involved in the antinociceptive action of TRH, the effects of pretreatment with either agonists or antagonists of noradrenaline (NA), dopamine and 5-hydroxytryptamine (5-HT), or naloxone were studied. TRH activity was generally resistant to modifications of NA, dopamine and 5-HT systems. The TRH effect was not antagonized by naloxone, but TRH at a non-analgesic dose presented the hyperalgesia induced by naloxone. 4 In conclusion, TRH i.c.v. possessed a short, strong antinociceptive activity against chemical and mechanical stimuli. This analgesia was at least equipotent to that of morphine i.c.v.