A role for presynaptic α2-adrenoceptors in angiotensin II-induced drinking in rats

Studies from this laboratory have shown that either central or peripheral administration of clonidine, the α₂-adrenoceptor agonist, can attenuate a variety of dipsogenic stimuli in rats. Further, yohimbine and tolazoline, α₂-adrenoceptor antagonists, augment the drinking response to both peripherally administered isoproterenol and angiotensin II. Studies reported here establish a dose-inhibition relationship between the dose of clonidine administered (2 to 32 μg/kg) intracerebroventricularly (IVT) and inhibition of the drinking response to peripherally administered angiotensin II (200 μg/kg, SC). DI₅₀ was approximately 4 μg/kg. Yohimbine (300 μg/kg, SC) reversed the antidipsogenic effect of centrally administered clonidine (32 μg/kg, IVT) on angiotensin II-induced (200 μg/kg, SC) water intake. Phenylephrine, an α₂-adrenoceptor agonist, administered IVT (40 and 80 μg/kg) also inhibited angiotensin II-induced drinking in a dose-related fashion. The antidipsogenic effect of phenylephrine (80 μg/kg) was blocked by administration of yohimbine (300 μg/kg, SC). Thus, this effect of phenylephrine most likely occurs by way of α₂-adrenoceptors. These results support a role for the pre-synaptic α₂-adrenoceptor in the mediation of drinking in rats. Activation of α₂-adrenoceptors is accompanied by reduced water intake while inhibition of these receptors enhances water intake.     

Antidipsogenic effect of clonidine on angiotensin II-, hypertonic saline-, pilocarpine- and dehydration-induced water intakes

The dipsogenic responses of female rats to administration of angiotensin II (150 μg/kg b.w., IP), pilocarpine (3 mg/kg/IP), hypertonic saline (1 M NaCl solution, 1% b.w.), and a 24 hour dehydration were attenuated by acute IP administration of graded doses of the central and peripheral α₂-adrenergic agonist, clonidine. For all treatments except dehydration, clonidine inhibited significantly the dipsogenic response at the lowest dose used (6 μg/kg, IP). The first significant effect on dehydration-induced drinking required approximately a 4 fold higher dose (25 μg/kg, IP). Attenuation of the response to these dipsogenic stimuli by clonidine, suggests that its ability to stimulate α-adrenergic receptors centrally may play an important role in its dipsogenic inhibitory activity.     

Effect of acute administration of isoproterenol and angiotensin II, separately and in combination, on water intake and blood pressure of rats

The effects of administration of isoproterenol, a β-adrenergic agonist, and angiotensin II, a peptide, separately and in combination, on water intake and blood pressure of rats were studied. The results of 6 factorially designed studies in which 4 different doses of each compound were administered revealed that water intakes increased directly with the logarithm of increasing doses of each. The effect of simultaneous administration of the 2 compounds on water intake was additive at submaximal doses of each. No interactive effects on water intake were observed when the 2 compounds were administered simultaneously in any study. Reduction in urine output appears to be a more sensitive response to administration of isoproterenol than increase in water intake since it was virtually abolished at a dose (2.5 μg/kg SC) that had no effect on water intake. The lowest doses of angiotensin II (25 and 50 μg/kg SC) had no significant effect on either water intake or urine output. The effect of simultaneous administration of both compounds on urine output was essentially the same as that accompanying administration of isoproterenol alone. Following administration of angiotensin II (150 μg/kg, SC) mean systemic blood pressure of unanesthetized, chronically cannulated rats reached maximal levels within 5 min and returned to pretreatment control level by 60 min. Following administration of isoproterenol (25 μg/kg, SC), mean systemic blood pressure decreased within 5 min, was maximally depressed by 30 min and had returned halfway to the pretreatment control level by 60 min. Simultaneous administration of isoproterenol and angiotensin II failed to induce a significant change in blood pressure. These results are of particular interest since they show that neither the pressor effect of angiotensin II nor the depressor effect of isoproterenol is essential for the induction of drinking by these 2 compounds.     

Effects of yohimbine and tolazoline on isoproterenol and angiotensin II-induced water intake in rats

Subcutaneous administration of the α₂-adrenoreceptor antagonists, yohimbine and tolazoline, at doses up to 1000 μg/kg, had no effect on water intake of female rats. However, when these compounds were administered SC in combination with either the β-adrenoreceptor agonist, isoproterenol (10 to 25 μg/kg, SC), or with angiotensin II (200 μg/kg, SC), water intake was enhanced. In contrast, intraventricular administration of either tolazoline (10 and 20 μg/kg) or yohimbine (300 μg/kg) failed to augment the dipsogenic response to angiotensin II (150 μg/kg, SC). Thus, the enhancing effect of these α₂-adrenoreceptor antagonists on isoproterenol- and angiotensin II-induced water intakes appears to be manifested peripherally, rather than centrally. In view of the fact that clonidine, an α₂-adrenoreceptor agonist, has been shown to inhibit water intake induced by both isoproterenol and angiotensin II, the results suggest that the α₂-adrenoreceptor may play a role in modulating water intake induced by these two dipsogenic agents.     

Activation of central μ-opioid receptors is involved in clonidine analgesia in rats

The analgesic effect of clonidine in spontaneously hypertensive rats (SHR) and in normotensive Sprague-Dawley (SD) rats was assessed by using the formalin pain test. The analgesic response of SD rats to low doses (15–60 μg/kg i.p.) but not to a high dose (150 μg/kg i.p.) of clonidine was inhibited by naloxone, 2 mg/kg i.p., and a similar interaction was noted in SHR. In both rat strains, the analgesic response to low i.p. doses of clonidine was also inhibited by injection of 5 μg of naloxone or 7 μg of β-funaltrexamine, a μ-receptor antagonist, into the lateral cerebral ventricle. I.c.v. injection of 5 μg of ICI 174864, a δ-receptor antagonist, potentiated or did not influence clonidine analgesia in SD rats and SHR, respectively. It is concluded that the analgesic response to clonidine involves activation of central μ-opioid receptors in both SHR and SD rats, possibly by an endogenous opioid released by clonidine.     

Cardiovascular effects of intravenous administration of clonidine in conscious cats

We previously reported that cardiovascular effects elicited by intracerebroventricular (i.c.v.) administration of clonidine result from stimulation of central α₂-adrenergic and/or H₂-histaminergic receptors, but not via activation of I₁-imidazoline receptors in conscious cats. In this study, we investigated the effects on arterial blood pressure (MAP) and heart rate (HR) following an intravenous (i.v.) administration of clonidine using conscious cats. Injection of clonidine (2–10 μg/kg i.v.) elicited a decrease in mean arterial pressure (MAP) and heart rate (HR) dose-dependently. The dose of 10 μg/kg of clonidine decreased MAP and HR by 30±4 mmHg and 62±15 bpm, respectively. Intravenous or i.c.v. pretreatment with yohimbine, the α₂-adrenoceptor and 5-HT_1A receptor antagonist, blocked the cardiovascular responses to a subsequent i.v. injection of 10 μg/kg clonidine. However, i.v. or i.c.v. preadministration of cimetidine, the H₂-histamine receptor antagonist, failed to antagonize the decreases in MAP and HR to a subsequent i.v. injection of 10 μg/kg clonidine. In addition, i.c.v. or i.v. pretreatment with the I₁-imidazoline receptor blocker, efaroxan, failed to inhibit the cardiovascular effects of an i.v. administration of clonidine. These results demonstrate that i.v. clonidine evokes decreases in MAP and HR possibly via central α₂-adrenoceptor and/or 5-HT_1A receptors and not through H₂-histamine or I₁-imidazoline receptors.     

Differential modulation of angiotensin II and hypertonic saline-induced drinking by opioid receptor subtype antagonists in rats

Opioid modulation of ingestion includes general opioid antagonism of different forms of water intake, μ₂ receptor modulation of deprivation-induced water intake and δ₂ receptor modulation of saccharin intake. Water intake is stimulated by both central administration of angiotensin II (ANG II) and peripheral administration of a hypertonic saline solution; both responses are reduced by general opioid antagonists. The present study examined whether specific opioid receptor subtype antagonists would selectively alter each form of water intake in rats. Whereas systemic naltrexone (0.1–2.5 mg/kg, s.c.) reduced water intake induced by either peripheral ANGII (500 μg/kg, s.c.) or hypeptonic saline (3 ml/kg, 10%), intracerebroventricular (i.c.v.) naltrexone (1–50 μg) only inhibited central ANGII (20 ng)-induced hyperdipsia. Both forms of drinking were significantly and dose-dependently inhibited by the selective κ antagonist, nor-binaltorphamine (Nor-BNI, 1–20 μg). Whereas both forms of drinking were transiently reduced by the μ-selective antagonist, β-funaltrexamine (β-FNA, 1–20 μg), the μ₁ antagonist, naloxonazine (40 μg) stimulated drinking following hypertonic saline. The δ₁ antagonist, [d-Ala², Leu⁵, Cys⁶]-enkephalin (DALCE, 1–40 μg) significantly reduced drinking following ANGII, but not following hypertonic saline; the δ antagonist, naltrindole failed to exert significant effects. These data indicate that whereas κ opioid binding sites modulate hyperdipsia following hypertonic saline, μ₂, δ₁ and κ opioid binding sites modulate hyperdipsia following ANGII. The μ₁ opioid binding site may normally act to inhibit drinking following hypertonic saline.     

Effects of morphine and morphine withdrawal on adrenergic neurons of the rat rostral ventrolateral medulla

In urethane anesthetized rats, iontophoretic application of morphine or α-methylnoradrenaline (α-MNE) inhibited (80–100%) the discharges of all putative adrenergic (C1) cells of the rostral ventrolateral medulla (RVLM). The effect of morphine was blocked selectively by naloxone while that of α-MNE was blocked selectively by theα₂-adrenergic antagonist idazoxan. Putative C1 cells were inhibited (75–100%) by low i.v. doses of clonidine (10–15 μg/kg). Most cells (7/10) were also inhibited by morphine i.v. (81% at 7 mg/kg). Two cells were slightly excited at doses below 2 mg/kg and inhibited at higher doses. Three cells were excited only. All effects of morphine i.v. were reversed by naloxone (1 mg/kg, i.v.). Intravenous administration of naloxone to morphine-dependent rats increased significantly the firing rate of all putative C1 adrenergic cells (from 5.8 ± 0.9 spikes/s to 12.3 ± 1.5 spikes/s;n = 8). During withdrawal these cells could still be inhibited (80–100%) by i.v. injection of clonidine (15 μg/kg). C-Fos expression induced by naltrexone-precipitated withdrawal was examined in the brainstem of freely moving morphine-dependent rats pretreated with clonidine or saline before injection of the opioid antagonist. The locus coeruleus (LC) of the same rats was examined for comparison. Morphine withdrawal without clonidine treatment significantly increased the number of Fos-like-immunoreactive (Fos-LIR) cells in the RVLM and LC. Clonidine pretreatment (1 mg/kg, i.p.) reduced the number of withdrawal-activated Fos-LIR cells in LC by 81%. In the RVLM this reduction averaged 37% for all cell types and 48% for C1 adrenregic cells. Further, a very large proportion of RVLM neurons that expressed c-Fos during morphine withdrawal (83%) were immunoreactive forα₂A-adrenergic receptors. This study suggests that, like noradrenergic cells of the LC, C1 adrenergic neurons of the RVLM are: (i) inhibited by both opiate andα₂-adrenergic receptor agonists; and (ii) activated during naloxone-precipitated morphine withdrawal, Since C1 cells are considered essential to sympathetic tone generation, their inhibition by morphine may contribute to the hypotensive effects of this opioid agonist in non-dependent individuals. Their excitation during opiate withdrawal may also contribute to the autonomic activation that characterizes this syndrome. Finally, inhibition of C1 cells by clonidine may contribute to the clinically recognized efficacy of this drug to attenuate autonomic signs of opiate withdrawal.     

Cardiovascular effects of central administration of clonidine in conscious cats

The effects on arterial blood pressure and heart rate after an intracerebroventricular (i.c.v.) administration of clonidine were investigated using conscious normotensive cats. Injection of clonidine (5–10 μg; 5 μl; i.c.v.) elicited a decrease in mean arterial pressure (MAP) and heart rate (HR) in a dose-dependent manner. The highest dose of 10 μg of clonidine decreased MAP and HR by 39 ± 3 mmHg and 74 ± 5 b.p.m., respectively (n = 7). Pretreatment with yohimbine, the α₂-adrenoceptor antagonist (8 μg; 5 μl; i.c.v.) blocked the cardiovascular responses to a subsequent i.c.v. injection of 10 μg clonidine (n = 7). Furthermore, preadministration of cimetidine (100 μg; 5 μl; i.c.v.), the H₂ histamine receptor antagonist with imidazoline receptor activating properties, prevented the decreases in MAP and HR to a subsequent i.c.v. injection of 10 μg clonidine (n = 7). By contrast, pretreatment with the specific I₁ imidazoline receptor blocker, efaroxan (100–500 μg; 5 μl; i.c.v.), failed to inhibit the cardiovascular effects of an i.c.v. administration of 10 μg clonidine (n = 7). These results suggest that the effects of centrally administered clonidine on MAP and HR are probably not mediated through activation of the I₁ subtype of imidazoline receptors in conscious cats. However, the cardiovascular effects elicited by i.c.v. administration of clonidine appear to result from stimulation of central α₂-adrenergic or the H₂ histaminergic-like receptors.     

Depression by morphine-6-glucuronide of nociceptive activity in rat thalamus neurons: comparison with morphine

To assess the contribution of the active metabolite of morphine, morphine-6-glucuronide (M6G), to the analgesic effect of systemically administered morphine, experiments were carried out on rats under urethane anesthesia in which nociceptive activity was evoked by electrical stimulation of afferent C fibers in the sural nerve and recorded from single neurons in the ventrobasal complex of the thalamus. Intravenous (i.v.) injections of morphine completely blocked the activity at doses of 500 and 1000 μg/kg, the ED,, being 44 μg/kg. M6G administered by i.v. injection reduced the evoked nociceptive activity only by about 40% at 80 and 160 μg/kg, the ED₅₀ being 6 μg/kg. After intrathecal (i.t.) injection, morphine produced maximum depression of 55% of the control activity at 20 μg the ED₅₀ is 18 μg. M6G injected i.t. produced maximum depression of 40% at doses ranging from 0.2 to 10 μg. The ED₅₀ of M6G i.t. is below 0.2 μg. The effects of morphine and M6G were reversed by naloxone (200 μg/kg i.v.). The results show that M6G is more potent than morphine, regardless of the route of administration, while morphine is more effective when injected i.v. Due to the low efficacy of M6G, it seems unlikely that this glucuronide contributes substantially to the analgesic effect of morphine when renal function is normal. The results also make evident that the maximum effect of morphine results from an action at spinal and supraspinal sites.     

Beneficial effect of i.c.v. naloxone in anaphylactic shock is mediated through peripheral β-adrenoceptive mechanisms

In mice, fatal shock induced by release of endogenous histamine by compound 48/80 was reversed by the intracerebroventricular (i.c.v.) administration of the opiate antagonist naloxone (10–25 μg) but not by the systemic administration of the selective peripherally acting antagonist, naltrexone methyl bromide (2–5 mg/kg). Moreover, systemac or i.c.v. administration of morphine (25 mg/kg and 25 μg, respectively) exacerbated shock induced by compound 40/80. This effect was blocked by i.c.v. naloxone (10 μg) or naltrexone methyl bromide (10 μg) but not by systemic naltrexone methyl bromide (5 mg/kg). The pathogenic effect of i.c.v. morphine was blocked by the systemic administration of the opiate antagonist Win 44,441-3 (5 mg/kg) but not by its inactive (+) isomer, Win 44,441-2. The results suggest possible involvement of central opiate (endorphin) mechanisms in the pathophysiology of fatal histamine shock in mice.     

Noradrenergic afferents to median eminence: Inhibitory role in rhythmic growth hormone secretion

The involvement of noradrenergic (NA) afferents to the median eminence (ME) in the regulation of growth hormone (GH) secretion was investigated in chronically cannulated, unanaesthetized male rats by using systematically administered 6-hydroxy-dopamine (6-OHDA).One day after 6-OHDA treatment (50 mg/kg, i.v.) GH peak frequency was substantially increased and examination of catecholamine (CA) fluorescence indicated disruption of CA innervation of the ME, but not other central nervous system (CNS) structures. Prolactin secretion at this time was normal and the administration of butaclamol (1.0 mg/kg, i.v.), a dopamine (DA) antagonist, was effective in increasing secretion, indicating that ME DA mechanisms were functionally intact following 6-OHDA treatment. GH secretory patterns returned to normal by 21 days following 6-OHDA treatment and this corresponded with re-emergence of a normal pattern of CA-fluorescence in the ME.In an additional study, the administration of the α-NA agonist clonidine (130 μg/kg, i.v.) increased GH secretion in previously untreated animals. Administration of the α-NA agonist oxymetazoline (45 μg/kg, i.v.), which does not readily pass the blood-brain barrier (BBB), suppressed GH secretion.These findings indicate that ME NA afferents are inhibitory to GH secretion and are a major determinant of the 3 h pattern of GH release in the rat. This inhibitory input is subsidiary to a NA stimulatory input to an as yet unidentified site inside the BBB.     

Cardiovascular effects elicited by central administration of physostigmine via M2 muscarinic receptors in conscious cats

The cardiovascular effects of an intracerebroventricular (i.c.v.) injection of physostigmine were studied using conscious cats. Physostigmine (5–25 μg: 5 μl) caused a dose-dependent increase in mean arterial pressure (MAP) and heart rate (HR). The highest dose (25 μg) increased MAP and HR by 32 ± 3 mmHg and 45 ± 5 beats/min, respectively (n = 5). Pre-administration of the muscarinic receptor antagonist, atropine (25 μg; i.c.v.) blocked the effects of physostigmine (25 μg; i.c.v.). Also, the pre-administration of the M₂ muscarinic antagonist, methoctramine (25 μg; i.c.v.), antagonized the cardiovascular effects of physostigmine without altering the baseline variables. However, the M₁ muscarinic antagonist, pirenzepine (100 μg; i.c.v.) did not alter baseline MAP or HR, and also failed to inhibit the cardiovascular responses to physostigmine. Similarly, the M₃ muscarinic blocker, 4-diphenyl-acetoxy-N-methylpiperidine methiodide (50 μg; i.c.v.), neither changed baseline cardiovascular variables nor blocked the effects of physostigmine. When the same cats were anesthetized with intravenous injection of sodium pentobarbital (25–30 mg/kg), physostigmine (25 μg; i.c.v.) evoked a decrease in MAP and HR of 13 ± 6 mmHg and 15 ± 6 bpm, respectively (n = 5). These results demonstrate that the increases in MAP and HR to the i.c.v. administration of physostigmine in conscious cats arepossibly mediated through stimulation of central M₂ muscarinic receptors. In addition, anesthesia reverses the effects elicited by the central administration of physostigmine to a decrease in MAP and HR.     

Elevation of plasma ACTH concentration in rabbits made febrile by systemic injection of bacterial endotoxin

This study was carried out to investigate the adrenocorticotrophic hormone (ACTH) response in rabbits made febrile by systemic injection of lipopolysaccharide (LPS,Salmonella typhosa endotoxin). Intravenous (i.v.) injection of LPS (0.1 μg/kg and 1.0 μg/kg) increased rectal temperature (biphasic fever) and the plasma concentration of ACTH (ACTH response) in a dose-related manner. These responses were suppressed by pretreatment with indomethacin (20 mg/kg, subcutaneously). Intracerebroventricular (i.c.v.) administration of indomethacin (400 μg) had no effect on the ACTH response to LPS, although it significantly suppressed febrile response. Small increases in plasma concentration of ACTH and significant fevers followed i.c.v. administration of prostaglandin E₂ (2 μg) or F_2α (2 μg). I.v. administration of corticotropin releasing factor (CRF) antagonist [α-helical CRF (9–41) (200 μg/kg)] partly suppressed the ACTH increased induced in plasma by i.v. LPS. These results suggest that prostagandins synthesized outside the blood-brain barrier play an important role in the ACTH response and that the mechanism for induction of the ACTH response is not exactly the same as that for the febrile response, although prostaglandins are involved in both responses.     

Effects of intracerebroventricularly administered chimeric peptide of metenkephalin and FMRFa—[D-Ala]YFa—on antinociception and its modulation in mice

An enzymatically stable analog of YGGFMKKKFMRFamide (YFa), a chimeric peptide of metenkephalin and FMRFa, was synthesised. The antinociceptive effects of intracerebroventricular injections of this analog—[D-Ala²]YAGFMKKKFMRFamide ([D-Ala²]YFa)—was then investigated using the mouse radiant-heat tail-flick test. [D-Ala²]YFa produced modest to good antinociception at 1, 2, and 5 μg/mouse (0.64, 1.28, and 3.22 nmol, respectively). This antinociceptive effect was completely reversed by the opioid receptor antagonist naloxone (1.5 μg/mouse: 4.12 nmol, intracerebroventricular [i.c.v.]), administered 5 min prior. Pretreatment (5 min) with either neuropeptides FF (1 μg/mouse: 0.92 nmol, i.c.v.) or FMRFa (1 μg/mouse: 1.69 nmol, i.c.v.) significantly attenuated the antinociceptive effects induced by [D-Ala²]YFa (1 μg/mouse, i.c.v.). Intracerebroventricular administration of [D-Ala²]YFa at 1 μg/mouse dose with morphine (2 μg/mouse: 5.86 nmol, i.c.v.) produced an additive antinociceptive effect, suggesting that [D-Ala²]YFa may have a modulatory effect on opioid (morphine) analgesia. These results provide further support for a role of such amphiactive sequences in antinociception and its modulation.     

The peripheral nociceptive actions of intravenously administered 5-HT in the rat requires dual activation of both 5-HT2 and 5-HT3 receptor subtypes

In 16-week-old Sprague-Dawley rats lightly anesthetized with pentobarbital, 5-HT (3–96 μg/kg, i.v.;n = 6) produced distinct pseudaffective responses and a dose-dependent (slope= 17.2 ± 6.8s/log₁₀dose) inhibition of the tail-flick (TF) reflex (ED₅₀ = 32.6 ± 9.2 μg/kg). In the same rats, a 1:1 combination of α-methyl 5-HT (a 5-HT₂ receptor selective agonist) and 2-methyl 5-HT (a 5-HT₃ receptor selective agonist) (3–192 μg/kg, i.v.), produced the same profile of pseudaffective responses and also resulted in a dose-dependent (slope= 34.0± 7.0s/log₂dose) inhibition of the TF reflex (ED₅₀ = 88.4 ± 20.5 μg/kg). In contrast, administration of α-methyl 5-HT (3–192 μg/kg, i.v.) or 2-methyl 5-HT (3–192 μg/kg, i.v.) alone did not produce any pseudaffective responses or any change in TF latency from baseline. In conscious 16-week-old male Sprague-Dawley rats, administration of 5-HT (48 μg/kg, i.v.;n = 5), or a 1:1 combination of α-methyl 5-HT and 2-methyl 5-HT (total dose= 120 μg/kg, i.v.;mn = 5), resulted in a passive avoidance behavior assessed in a step-down paradigm (slopes= 139.7 ± 58.2and154.9 ± 63.9s/trial, respectively), and the same profile of distinct pseudaffective responses exhibited by the lightly pentobarbital-anesthetized rats. However, administration of either α-methyl 5-HT (96 μg/kg, i.v.;n = 4) or 2-methyl 5-HT (96 μg/kg, i.v.;n = 4), while producing significant 5-HT receptor-mediated cardiovascular responses, produced a learned behavior not different from saline (0.25 ml, i.v.;n = 6) (slopes= 7.6 ± 2.5, 6.3 ± 1.8and7.4 ± 3.6s/trial, respectively). These results are consistent with the hypothesis that the peripheral nociceptive responses to i.v. 5-HT requires dual activation of 5-HT₂ and 5-HT₃ receptor subtypes.     

Evidence for central α2-adrenergic modulation of rat pineal melatonin synthesis

This study was performed to distinguish central and peripheral α₂-adrenoceptors in the inhibition of rat pineal melatonin synthesis. The rats received lipo- or hydrophilic α₂-adrenoceptor ligand injections at middark; after 1 or 2 h the pineal melatonin contents were measured. The lipophilic agonist medetomidine (100 μg/kg s.c.) suppressed the melatonin contents significantly, while the hydrophilic agonists ST-91 and p-aminoclonidine (10 or 100 μg/kg i.v.) did not. The suppression by medetomidine was counteracted by the lipophilic antagonist yohimbine (0.3–3.0 mg/kg i.p.) but not by the hydrophilic antagonist L-659,066 (1–10 mg/kg i.v.). In conclusion, the suppression of nocturnal melatonin synthesis by α₂-adrenoceptor agonists is mainly of central origin.     

The effects of desipramine (DMI) and alpha-2 adrenoceptor agonists on flexor reflex activity (FRA) in the spinalized and decerebrate rat

Summary In the spinalized and decerebrate rat, electrically evoked flexor reflex activity (FRA) of the right anterior tibialis muscle was facilitated by DMI (0.1–3 mg/kg i.v.). DMI (3 mg/kg i.v.) had not effect on twitches of the left ant. tib. muscle evoked by electrical stimulation of the distal stump of the severed sciatic nerve (directly evoked twitches). The alpha-1 adrenoceptor antagonist prazosin (300 g/kg i.v.) and the alpha-2 adrenoceptor agonists clonidine (5 and 10 g/kg i.v.) and BHT-920 (100 g/kg i.v.) all suppressed FRA facilitated by DMI (3 mg/kg i.V.). The alpha-2 adrenoceptor antagonists yohimbine (100 g/kg i.v.) and mianserin (30 g/kg i.v.) antagonized the suppressant effect of clonidine (5 g/kg i.v.) on DMI-facilitated FRA. Clonidine (10 g/kg i.v.) had no effect on directly evoked twitches, and at 3–300 g/kg i.v. had no effect on FRA facilitated by L-DOPA (100 mg/kg i.p.). It is suggested that DMI-facilitated FRA can be used as a test for alpha-2 adrenoceptor agonists which may act at presynaptic alpha-2 adrenoceptors in the spinal cord.     

Differential effects of IL-1ra on sickness behavior and weight loss induced by IL-1 in rats

Peripheral and central injections of recombinant human interleukin-1β (IL-1β) have been shown to decrease social exploration and to induce body weight loss in rats. To characterize the receptor mechanisms of these effects, we used as a tool a specific antagonist of the receptors of IL-1, IL-1ra. Intraperitoneal (i.p.) administration of IL-1ra (8 mg/kg) blocked the effect of i.p. injection of IL-1β (4 μg/rat) on social behaviour but not on body weight. Central administration of IL-1ra (60 μg/rat, i.c.v.) abrogated the effects of centrally administered IL-1β (30 ngn/rat, i.c.v.) on both social behaviour and body weight. Central injection of IL-1ra (4 μg/rat, i.c.v.) also attenuated the effects of i.p. administered IL-1β (4 μg/rat) on social behaviour but not on body weight. These results suggest that the effects of IL-1β on social behavior are mediated centrally and that its effect on the loss of body weight involves different receptor mechanisms.     

Modification of morphine-induced locomotor activity by pertussis toxin: biochemical and behavioral studies in mice

The effect of pertussis toxin (PTX) on the locomotor-enhancing action of systemic and intracerebroventricular (i.c.v.) morphine was investigated in mice. Mice were i.c.v. injected with either PTX (0.25 and 0.5 μg) or saline as a control. The s.c. (5–20 mg/kg) and i.c.v. (7–30 nmol) administration of morphine produced a dose-related locomotor-enhancing action in control mice. The peak effect of morphine (30 nmol, i.c.v.)-induced hyperlocomotion was observed 90 min after the morphine injection. At the same time, morphine significantly increased dopamine (DA) metabolism in the limbic forebrain (nucleus accumbens and olfactory tubercle). Similarly, the selective μ-opioid receptor agonist[d-Ala²,N-MePhe⁴,Gly-ol⁵]enkephalin (DAGO, 4 nmol, i.c.v.) also significantly increased locomotor activity and DA metabolism in the limbic forebrain. Both morphine- and DAGO-induced hyperlocomotion and elevation of DA turnover were antagonized by pretreatment with the μ antagonist β-funaltrexamine (β-FNA). These results suggest that the locomotor-enhancing action of morphine results from the activation of central μ-opioid receptors, and that the activation of the mesolimbic DA system may be involved in the expression of morphine-induced hyperlocomotion in mice. Furthermore, pretreatment with PTX (0.5 μg, i.c.v., 6 days prior to the testing) significantly reduced hyperlocomotion and elevation of DA turnover in the limbic forebrain which had been induced by administrations of morphine (30 nmol, i.c.v.) and DAGO (4 nmol, i.c.v.). These findings suggest that the central PTX-sensitive GTP-binding protein (G-protein) mechanism may play an important role in opioids-induced locomotor-enhancing action. Furthermore, the activation of mesolimbic DA transmission by μ-opioid agonists may also be mediated by a PTX-sensitive G-protein mechanism in mice.