Influence of diazepam,l-dopa and dopamine on the cerebellar and spinal electrical patterns induced by harmine in the rabbit

The effects of harmine on the electrical activity of the cerebellum and spinal cord were studied in the rabbit. Harmine (2 mg/kg, i.v.) induced bursts of spikes at 10 Hz in the cerebellar vermis and synchronous waves in the spinal leads. Activation of the EEG was recorded from the cortical cerebral leads. Diazepam (1 mg/kg) administered either before or after harmine, blocked the spinal seizures without influencing the cerebellar spiking. l-Dihydroxyphenylalanine (5–10 mg/kg) antagonized the harmine tremors but did not modify the EEG. Dopamine (10mg/kg) blocked but did not prevent harmine tremors. Dopamine did not influence the EEG changes induced by harmine.     

Time schedule of apomorphine administration determines the degree of globus pallidus excitation

Intravenous administration of a single 320 μg/kg bolus of apomorphine signicantly increased the unit activity of rat globus pallidus neurons. Significantly attenuated responses to apomorphine were observed when 320 μg/kg apomorphine was administered i.v. in divided doses (5, 35, 280 μg/kg) 3–5 min apart of when 320 μgg/kg apomorphine was given i.v. 8 min after nonexcitatory ‘priming’ dose (20 μg/kg i.v.) of apomorphine. These results suggest that the expression and magnitude of apomorphine-induced excitation of pallidal neurons is influenced by the time schedule of drug administration.     

Nitecapone and selegiline as effective adjuncts to L-DOPA in reserpine-induced catatonia in mice

Reserpine-induced catatonia is a widely accepted animal model of Parkinson's disease. In the present study, reserpine (5 mg/kg i.p.) and alpha-methylpara-tyrosine (AMPT) (200 mg/kg i.p.) induced catatonia in mice 20 h and 1 h before the experiment, respectively, as assessed using the rota-rod and bar tests after reserpine treatment. There was a significant decrease in fall-off time in the rota-rod test and a significant increase in time spent on the bar in the bar test as compared to the untreated control mice. Combination therapy with L-DOPA (100 mg/kg i.p.) and carbidopa (10 mg/kg i.p.) was less effective in reversing catatonia as compared to higher doses of L-DOPA (200 mg/kg i.p.) and carbidopa (20 mg/kg i.p.), which showed intense hyperactivity in reserpinized mice. Pretreatment with nitecapone (30 mg/kg i.p.), a COMT inhibitor, or selegiline (10 mg/kg i.p.), a MAO-B inhibitor potentiated the motor stimulant actions of subthreshold doses of the L-DOPA (100 mg/kg i.p.) and carbidopa (10 mg/kg i.p.) combination. Amantadine (40 mg/kg i.p.), but not bromocriptine, potentiated the effects of L-DOPA treatment. The NMDA antagonistic action of amantadine may have beneficial effects. It is concluded that COMT and MAO-B enzymes play an important role in the metabolism of dopamine and administration of a COMT or MAO-B inhibitor may prove to be a better adjunct to L-DOPA therapy than a dopamine receptor agonist in Parkinson's disease.     

Interaction of central serotonin and dopamine in the regulation of carbaryl-induced tremor.

Carbaryl (50-200 mg/kg, p.o.) produced dose-dependent tremors and inhibition of striatal AChE activity. A dose-dependent elevation of striatal 5-HT and 5-HIAA levels was also observed with carbaryl but at the higher doses (100-200 mg/kg p.o.). L-Trp or 5-HTP or haloperidol potentiated the carbaryl-induced tremors. Further, 5-HTP or haloperidol, when administered (i) alone, reduced the ED50 value and increased the duration of carbaryl-induced tremors without affecting the maximum tremorogenic response of rats and (ii) together, did not change any of these measures significantly. Atropine (acetylcholine antagonist) completely blocked the tremors produced by carbaryl in the absence or presence of 5-HTP or haloperidol. Methysergide (5-HT antagonist) and bromocriptine (DA agonist) antagonised the potentiating effect of 5-HTP and haloperidol, respectively, on the carbaryl-induced tremors. Furthermore, bromocriptine antagonised the potentiating effect of 5-HTP on the carbaryl-induced tremor but, methysergide failed to achieve this antagonism in presence of haloperidol. These results indicate that carbaryl-induced tremors primarily involve the activation of central cholinoceptors and that the serotonergic potentiation of carbaryl-induced tremors is possibly mediated through the dopaminergic disinhibition of cholinergic neurons.     

The potentiation of the activity of adenosine on coronary blood flow, blood pressure and heart rate by inosine in the dog.

The activity of adenosine and inosine on coronary blood flow and arterial blood pressure was investigated in anaesthetized and thoracotomized dogs. The following results were obtained. 1. Individual adenosine administration caused an increase in coronary blood flow. However, this adenosine activity was significantly strengthened when the same dose of adenosine was applied simultaneously with inosine in doses of 3.2, 5.6 and 10.0 mg/kg body weight i.v. The duration of the effect of adenosine on the coronary blood flow was also potentiated by inosine. 2. The hypotensive effect resulting from 0.2 mg adenosine/kg i.v. was significantly strengthened by simultaneous inosine application (3.2, 5.6 and 10.0 mg/kg i.v.). The activities on the blood pressure of increments in the individual adenosine dosages (0.2, 0.4 and 0.6 mg/kg i.v.) were significantly potentiated by 10 mg inosine/kg body weight i.v. 3. The heart rate was not modified by 0.2 mg adenosine/kg i.v. However, the same adenosine dosage plus inosine (3.2, 5.6 and 10.0 mg/kg i.v.) applied simultaneously led to bradycardia. Increasing adenosine doses (0.2, 0.4 and 0.6 mg/kg i.v.) applied simultaneously with inosine (10.0 mg/kg body weight i.v.) led to a dose dependent retardation of the heart rate. 4. The possible reasons for the potentiation of the effect of adenosine by inosine were discussed.     

Endothelin antagonizes the hypotension and potentiates the hypertension induced by clonidine

Modification of clonidine-induced cardiovascular effects by endothelin-1 (ET-1) was studied in male Sprague-Dawley rats. A dose-dependent decrease in blood pressure and heart rate was produced by clonidine (100, 250 and 500 μg/kg i.v.). Lower doses produced only a fall in blood pressure (through central -adrenoceptors) while higher doses of clonidine produced an initial hypertensive response (through peripheral -adrenoceptors) and subsequent longer lasting hypotension and bradycardia. The hypotension and bradycardia induced by 100 and 250 μg/kg i.v. dose of clonidine were completely blocked by ET-1 (100 ng/kg i.v.) pretreatment. Conversely, the hypertensive response induced by high dose of clonidine (500 μg/kg i.v.) was significantly potentiated by ET-1 pretreatment. In cervical sectioned rats, i.v. administered clonidine failed to produce any hypotensive effect, indicating lack of central effect of clonidine. ET-1 significantly (P< 0.0005) potentiated the hypertensive response of a low dose (50μg/kg i.v.) of clonidine in cervical-sectioned rats. I.c.v administration of clodinine (1, 2, 4 and 6 μg) produced a dose-dependent decrease in blood pressure and heart rate. ET-1 pretreatment (25 ng i.c.v. transietly blocked the clonidine-induced decrease in blood pressure and heart rate for about 10 min but the hypotension and bradycardia was observed subsequently. Since the major site of action of clonidine is the ventral surface of medulla, clonidine was applied directly to the ventral surface of medulla and produced a decrease in blood pressure and heart rate. ET-1 pretreatment at the ventral surface of medulla blocked the clonidine-induced decrease in blood pressure and heart rate initially but the fall in blood pressure and heart rate was observed subsequently. To explore the possibility that transient antagonism of clonidine-induced effects is due to vasoconstriction, studies were performed with angiotensin II, a powerful vasoconstrictor. Angiotensin II (5 μg i.c.v.) pretreatment like ET-1 blocked the hypotensive and bradycardic effect of i.c.v. or i.v. administered clonidine. It is concluded that ET-1 blocks the hypotensive and potentiates the hypertensive effect of clonidine, possible mechanisms have been discussed.     

Effects of chlordiazepoxide, nicotine and d-amphetamine in the rat potentiated startle model of anxiety

The effects of acute administration of chlordiazepoxide (2.5 and 5.0mg/kg, i.p.), nicotine (0.05, 0.1 and 0.4mg/kg, s.c.) and d- amphetamine (0.5 and 1.0mg/kg, i.p.) on rat potentiated startle were investigated. Chlordiazepoxide, 2.5 and 5.0mg/kg, attenuated potentiation of startle, indicating an anxiolytic profile, although the effect of the higher dose was less marked and was accompanied by a reduction in overall startle response, probably reflecting drug-induced sedation. Nicotine at doses of 0.05 and 0.4mg/kg had no significant effects in this test. However, 0.1mg/kg nicotine eliminated potentiation of startle (in two separate experiments), an action comparable to that of 2.5mg/kg chlordiazepoxide. d-Amphetamine at doses of 0.5 and 1.0mg/kg did not significantly influence potentiation of startle. The results suggest that nicotine has an anxiolytic profile in the potentiated startle paradigm which is not due to its psychostimulant properties.     

Potentiation of disruptive effects of dextromethorphan by naloxone on fixed-interval performance in rats

A centrally acting antitussive agent dextromethorphan (DM) was tested to determine its possible interaction with naloxone in rats responding under a fixed-interval schedule of positive reinforcement. A sugar sweetened milk reward was used as a positive reinforcer. Under the same experimental conditions the effects of morphine alone and in combination with naloxone were also determined. Low dose DM (10 mg/kg) produced a slight increase, while higher doses (20–40 mg/kg) produced dose-dependent decreases in response rate. Morphine (0.3, 1.0 and 3.0 mg/kg) produced dose-dependent decreases in response rate. When doses of naloxone (0.1–1.0 mg/kg) were administered after the injection of DM the rate-decreasing effects of DM were potentiated even after the rate-increasing dose of naloxone (0.1 mg/kg) was used. When a dose of naloxone (0.1 mg/kg) was administered after the injection of morphine the rate-decreasing effects of morphine were markedly antagonized, i.e., the morphine dose-response curve was shifted to the right. The observed potentiation of DM disruption by naloxone on fixed-interval performance in rats is consistent with findings showing that naloxone potentiates the disruptive behavioral effects of a number of drugs that are psychotomimetic in man.     

Effects of nucleotide cyclase activators on the depressor response to selective low Km cyclic AMP phosphodiesterase inhibitors in rats

The potential interaction between agents which promote vasodilation through cyclic AMP (cAMP)- and cyclic GMP (cGMP)-dependent mechanisms was examined in conscious, spontaneously hypertensive rats (SHR). Selective inhibitors of low Km cAMP phosphodiesterase (PDE), CI-930 (0.1?10 mg/kg) and milrinone (0.03?3 mg/kg), were administered i.v. to SHR during a steady-state i.v. infusion of either the guanylate cyclase activator sodium nitroprusside (SNP, 5 or 15 μg/kg/min) or the adenylate cyclase activator fenoldopam (20 μg/kg/min). The depressor responses to Cl-930 and milrinone were significantly attenuated in the presence of SNP. This attenuation of the depressor response to Cl-930 was apparently not due to a hemodynamic floor effect since an equihypotensive dose of the calcium channel blocker verapamil (20 μg/kg/min infusion preceeded by a loading dose of 1.2 mg/kg i.v.) did not alter the response to Cl-930. The depressor response to Cl-930 was also attenuated during an infusion of fenoldopam, although this interaction was dependent upon the order of administration of these agents since pretreatment with Cl-930 (0.3 mg/kg, i.v.) potentiated the depressor response to infusions of fenoldopam (10 and 20 μg/kg/min). These data suggest that activation of either adenylate or guanylate cyclase may alter the intrinsic activity of low Km cAMP PDE and functionally impair the ability of inhibitors of this PDE isozyme to lower blood pressure. Furthemore, teh interactive effects of fenoldoparm and Cl-930 on blood pressure are dependent upon the order of administration.     

Antagonism by naloxone of anti-tremorine effect of bromocriptine in mice

Effects of the opioid antagonist naloxone (10 mg/kg) and its interaction with anticholinergic (scopolamine) and dopaminergic (bromocriptine) agents against tremorine-induced tremors was studied. Naloxone (10 mg/kg) per se gave significant protection and significantly potentiated the protective effect of scopolamine against tremorine-induced tremors at 5 min only. When naloxone and subeffective dose of bromocriptine (2 mg/kg) were administered simultaneously, instead of protection, an enhancement of tremorogenic activity was seen. Although the exact mechanism of this drug interaction is far from clear, a multireceptor involvement (i.e. opioid, dopaminergic and cholinergic type) in the modulation of tremorine-induced tremors in mice has been speculated.     

HETEROGENOUS ACTIVITY OF BRL 35135, A β3-ADRENOCEPTOR AGONIST, IN THERMOGENESIS AND INCREASED BLOOD FLOW IN BROWN ADIPOSE TISSUE IN ANAESTHETIZED RATS

1. The effects of BRL 35135, a β₃-adrenergic agonist, on body temperature and regional blood flow in brown adipose tissue (BAT) were simultaneously recorded in anaesthetized rats and compared to isoproterenol. 2. BRL 35135 at doses of 0.1 and 1 μg/kg (i.v.) induced dose-dependent increases in BAT temperature with minimal effects on systemic diastolic blood pressure (DBP), heart rate (HR) and BAT blood flow. 3. The thermogenic effect of BRL 35135 at a dose of 10 μg/kg (i.v.) was smaller than that at a dose of 1 μg/kg, and was accompanied by a marked increase in BAT blood flow. 4. Isoproterenol at doses of 0.01–1 μg/kg (i.v.) dose-dependently increased HR and BAT blood flow and decreased DBP. It did not affect BAT temperature. 5. These findings indicate that unlike isoproterenol, BRL 35135, at the lower doses, selectively causes thermogenesis in BAT which was detectable as changes in BAT temperature, and that the vasodilator effect in BAT is not as sensitive as the thermogenic effect of β₃-adrenergic agonists.     

Some in vitro and in vivo studies of a new angiotensin I-converting enzyme inhibitor [[S-(R*), S*]-1-[(3-acetylthio)-3-benzoyl-2-methylpropionyl]-L-proline] (CL 242,817) in comparison with captopril

Some in vitro and in vivo properties of CL 242,817, a new angiotensin l-converting enzyme (ACE) inhibitor, were studied and compared to those of captopril. In vitro CL 242,817 effectively inhibited rabbit lung ACE (IC50 54.9 nM), angiotensin l (Al)-induced contractions (IC50 0.82 μM), and potentiated bradykinin (BK)-induced contractions (EC50 0.383μM) of the guinea pig ileum. In these systems, CL 242,817 was approximately 3.5, 27, and 96 times less effective than captopril, respectively. In vivo, equimolar oral doses of CL 242,817 (8.36 mg/kg) and captopril (5 mg/kg) were equieffective in inhibiting the pressor responses to intravenously (i.v.) administered angiotensin l (Al) in normotensive rats and dogs. Similar equimolar oral doses of CL 242,817 and captopril were also equieffective in potentiating the depressor responses to i.v. administered BK in the rat. In the anesthetized dog 30 min after dosing, captopril (0.5 mg/kg i.v.) produced significantly greater potentiation of the BK response than a similar dose of CL 242,817. A single 1 mg/kg i.v. dose of Cl 242,817 or captopril effectively lowered mean arterial blood pressure of the aortic-coarcted hypertensive rat (AHR) and markedly inhibited serum ACE activity after 1 hr. Serum from AHR treated with CL 242,817 or captopril exhibited an apparent loss in ACE inhibition upon cold storage. However, the loss of inhibition of ACE activity was faster with captopril than with CL 242,817. Kinetic studies indicate that CL 242,817 is a pure competive inhibitor of ACE with an estimated Ki of 24.3 nM.     

Cholecystokinin octapeptide (CCK-8), ceruletide and analogues of ceruletide: effects on tremors induced by oxotremorine, harmine and ibogaine. A comparison with prolyl-leucylglycine amide (MIF), anti-Parkinsonian drugs and clonazepam

Cholecystokinin octapeptide (CCK-8), ceruletide (caerulein, CER) and 10 analogues of ceruletide, were studied in mice for antagonism of the tremors induced by harmine (5 mg/kg, s.c.), ibogaine (20 mg/kg, s.c.) and oxotremorine (0.2 mg/kg, s.c.). The following reference drugs were tested for comparison: prolyl-leucylglycine amide (MIF), atropine, haloperidol, biperiden, ethopropazine, trihexyphenidyl, methixene and clonazepam. All treatments were subcutaneous, the antagonists being given 10 min (in some trials 30 min) before the tremorogen. Tremorolytic potency (ED50) was calculated from dose-response curves. Against the tremors induced by either harmine or ibogaine, CCK-8 and ceruletide, as well as many of the analogues of ceruletide had greater tremorolytic potency than the reference drugs. Against oxotremorine, however, ceruletide and its most potent analogue, Nle8-CER (other analogues were not tested) were inactive and MIF showed very little effectiveness. Additional experiments on hypothermia and sedation as well as evaluation of previous studies on other central actions suggested that the tremorolytic effect of CCK-like peptides is independent of other central effects. The CCK-like peptides may play a physiological role in the regulation of extrapyramidal motor activity.     

Modification of naloxone-precipitated withdrawal symptoms in mice by drugs acting on alpha(2)-adrenoceptors

Modification of naloxone-precipitated withdrawal symptoms by drugs acting on alpha-adrenoceptors was investigated in morphine-dependent mice. Clonidine (0.05-1mg/kg) attenuated most withdrawal symptoms, but potentiated withdrawal hypothermia. Jumping was attenuated by doses of clonidine up to 0.3mg/kg, but markedly potentiated by 1mg/kg. Prazosin (0.05mg/kg) neither had effects of its own, nor influenced those of clonidine. Both yohimbine (0.05-5mg/kg) and idazoxan (1-10mg/kg) potentiated naloxone-precipitated withdrawal symptoms. When tested against a low dose of clonidine (0.2mg/kg), idazoxan dose-dependently reduced the suppressive effects of clonidine on jumping, "wet dog" shakes, burrowing and body-weight loss but potentiated the hypothermic response of clonidine. Yohimbine similarly reduced the suppressive effect of clonidine on body-weight loss and potentiated its hypothermic response, but unlike idazoxan, it did not influence the inhibition by clonidine of "wet dog" shakes, and markedly reversed the suppression of jumping and burrowing into potentiation. Yohimbine and idazoxan also differed with respect to their antagonistic profile against a high dose of clonidine (1mg/kg). Yohimbine further aggravated the potentiation of jumping by clonidine, reduced the effect on body-weight loss and reversed the suppression of burrowing by clonidine. On the other hand, idazoxan markedly reduced the potentiation of jumping by clonidine, and reversed its effect on "wet dog" shakes and burrowing. These findings indicate that clonidine has a biphasic effect on jumping, and disclose differences in the antagonistic profiles between yohimbine and idazoxan. The results suggest that in addition to alpha(2)-adrenoceptors, non-adrenergic imidazoline receptors sensitive to clonidine and idazoxan but not to yohimbine may modulate the expression of morphine withdrawal symptoms.     

Antagonistic activity of ascorbic acid (vitamin C) on dopaminergic modulation: apomorphine-induced stereotypic behavior in mice

Among the various neurotransmitter systems implicated in the mechanism of action of ascorbic acid (vitamin C), the relationship between the dopaminergic system and ascorbic acid is not particularly clear. Ascorbic acid is speculated to have an antagonistic effect on dopaminergic modulation. With this background in mind, in the present study we have seen the effect of ascorbic acid per se and in combination with typical and atypical antipsychotic agents against apomorphine-induced stereotypic behavior in mice. Male Laka mice weighing 20-25 g were used in the present study. Apomorphine-induced stereotypic behavior was used as an animal model. Various dopaminergic modulators were used. Ascorbic acid dose-dependently inhibited stereotypic behavior produced by apomorphine in mice. It potentiated the antipsychotic activity of haloperidol (0.1 mg/kg i.p.), a typical antipsychotic agent. When administered along with atypical antipsychotics, clozapine (1-2 mg/kg i.p.), sulpiride (10-20 mg/kg i.p.) and risperidone (0.0025 mg/kg i.p.), ascorbic acid also potentiated their activity. Also when given along with SCH-23390, a selective D(1) antagonist, an additive effect was observed. Ascorbic acid also inhibited the supersensitization response of apomorphine on reserpinization (2 mg/kg i.p.). Interestingly, at a lower dose (100 mg/kg i.p.), ascorbic acid potentiated the dopaminergic activity of apomorphine (0.5 mg/kg) and BHT-920 (0.25 mg/kg i.p.). However, when given concomitantly with SKF-38393, it failed to alter the response of SKF-38393. The data substantiate the hypothesis that ascorbic acid potentiated the activity of typical as well as atypical antipsychotics and that the effect of ascorbic acid on the dopaminergic system is markedly dose dependent; a low dose (100 mg/kg i.p.) potentiated the dopaminergic action while higher doses (400-1,600 mg/kg i.p.) blocked it.     

Behavioral and neurochemical effects induced by chronic L-DOPA administration

L-DOPA, in combination with benserazide, in the ratio 4:1 (w/w), was administered orally to rats. In the staircase maze test a low dose of L-DOPA (3 mg/kg/day) reduced the increase in errors caused by 20 days interruption of daily training, while a higher dose (30 mg/kg/day) was ineffective. A decrease in levels of dopamine in the olfactory system and DOPAC in the striatum was seen at all tested doses of L-DOPA, while an increase in 5-HT levels was seen in the hippocampus and in the striatum. 5-HIAA levels did not change. Levels of ACh in the olfactory system were reduced at all doses of L-DOPA, while in the hippocampus this effect was seen only at the dose of 90 mg/kg/day. The density of muscarinic receptors was not altered. AI1 tested doses of L-DOPA caused norepinephrine levels to fall in the hippocampus and increase in the striatum. The density of α₁-adrenoceptors was reduced only at the two lower doses of L-DOPA. A comparison of the neurochemical results with the behavioral modifications seen in the staircase maze test suggests that the catecolaminergic systems are implicated in the memory process.     

Captopril does not potentiate hypotension and algesia by substance P

Captopril (1-5 mg/kg, i.v.) did not affect the vasodepressor responses to substance P (1-30 micrograms/kg, i.v.) in anaesthetized rats. Substance P (100 micrograms/kg, s.c.) produced significant algesia in mice; this was not potentiated by the smaller doses of captopril (1-2 mg/kg, i.p.), but was instead antagonized by the high dose (5 mg/kg, i.p.). It is concluded that captopril does not have any influence on substance P degradation in vivo since the pharmacological actions of the undecapeptide are not enhanced after captopril treatment.     

Cardiovascular responses to combined treatment with selective monoamine oxidase type B inhibitors and L-DOPA in the rat

BACKGROUND AND PURPOSE: Postural hypotension is a common side-effect of L-DOPA treatment of Parkinson's disease, and may be potentiated when L-DOPA is combined with selegiline, a selective inhibitor of monoamine oxidase B (MAO-B). Rasagiline is a new, potent and selective MAO-B inhibitor, which does not possess the sympathomimetic effects of selegiline. We have studied the effects of these selective MAO inhibitors, L-DOPA and dopamine on the cardiovascular system of the rat. EXPERIMENTAL APPROACH: Blood pressure and heart rate was measured in conscious rats following acute or chronic administration of rasagiline, selegiline and L-DOPA, by comparison with the selective MAO-A inhibitor clorgyline, or the MAO-A/B inhibitor tranylcypromine. Cardiovascular responses, catecholamine release, and modification of pressor response to dopamine were studied in pithed rats. KEY RESULTS: In conscious rats neither rasagiline nor selegiline caused significant potentiation of the effects of L-DOPA (50, 100, 150 mg.kg(-1)) on blood pressure or heart rate at doses which selectively inhibited MAO-B, but L-DOPA responses were potentiated by clorgyline and tranylcypromine. In rats treated twice daily for 8 days with L-DOPA and carbidopa, selegiline (5 mg.kg(-1)) but not rasagiline (0.2 mg.kg(-1)) caused a significant hypotensive response to L-DOPA and carbidopa, although both drugs caused similar inhibition of MAO-A and MAO-B. In pithed rats, selegiline but not rasagiline increased catecholamine release and heart rate, and potentiated dopamine pressor response at MAO-B selective dose. CONCLUSIONS AND IMPLICATIONS: The different responses to the two MAO-B inhibitors may be explained by the amine releasing effect of amphetamine metabolites formed from selegiline.     

Etorphine induction of analgesia and catatonia in the rat: Systemic or intracranial injection

Etorphine was injected into the rat either intraperitoneally (i.p.), in the periaqueductal gray (PAG) region of the midbrain, or in the cerebellum (CB). The flinch-jump technique was used to measure analgesia and the bar test to assess catatonia. Etorphine doses were 5, 10, 50 or 100 μg/kg (i.p.). The doses of etorphine administered to the PAG were 0.1, 1.0, 2.0 or 3.0 μg. The dose of etorphine administered to the cerebellum was 2.0 μg. The effective doses into the PAG for producing both analgesia and catatonia were about 15 times less than the intraperitoneal doses, suggesting central mediation of these actions, involving the PAG and perhaps other central neural sites. Injection of 2.0 μg etorphine into the cerebellum did not cause analgesia or catatonia. There was a high correlation between the production of analgesia and of catatonia suggesting a common factor in these actions, at least as measured in this experiment.     

Effects of ACTH on pain responsiveness in mice: Interaction with morphine

Intravenous (i.v.) injections of ACTH either enhanced (12.5 μg/kg) or slightly, though not significantly, suppressed (200 μg/kg) jumping in a modified hot plate test (46°C, 5 min exposure) in mice. Similarly, injections of morphine (0.037–0.156 mg/kg) markedly enhanced jumping whereas larger doses (0.625–10.0 mg/kg) produced profound analgesia in this test. When administered simultaneously by a single intravenous injection, a larger dose of ACTH (200 μg/kg) blocked the hyperalgesic effect of the small dose of morphine (i.e. 0.037 mg/kg). A small dose of ACTH (12.5 μg/kg), which by itself produced significant hyperalgesia, prevented the analgesic action of morphine (0.625 mg/kg). Taken together, the data suggest that ACTH influences behaviourally-activated pain-controlling systems, possibly by interacting with opiate mechanisms in the brain. The ability of ACTH to alter the pharmacological actions of morphine as evident from the present results may be indicative of a requisite physiological function of ACTH in modulating the activity of endogenous opioids.