Effects of clopheline on impulse activity of neurons in the midbrain and dorsal horn of the spinal cord

Clophelin (1-5 mg/kg) suppresses spinal dorsal horn neuronal nociceptive responses but does not change their touch stimuli reactions in unanesthetized curarized cats. This effect is steady to naloxone (1 mg/kg), yohimbine (5 mg/kg) and removal by prazosin (1 mg/kg). Clophelin depresses nociceptive responses of the central gray matter neurones which generalized pain impulses in the supraspinal structures.     

Evidence for sedative effects of low doses of morphine in mice involving receptors insensitive to naloxone

Low doses of morphine (0.30–2.5 mg/kg) decrease in a dose-dependent manner spontaneous climbing behaviour in mice. This effect is not modified by administration of naloxone at doses up to 1.25 mg/kg. These morphine doses do not modify the locomotor activity but, when they are associated with naloxone (0.5 mg/kg), an obvious inhibition occurs. In rats, a hyperactivity follows the akinesia produced by a morphine administration (10 mg/kg). This hyperactivity is changed into a significant hypokinesia when the animals are treated with naloxone (0.05 mg/kg). These results might reveal a dual effect of low doses of morphine, the excitatory effect of morphine being antagonized by naloxone whereas no action on the sedative effect is observed.     

Naloxone attenuation of the effect of cocaine on rewarding brain stimulation

Antagonism of the threshold lowering effect of cocaine for brain stimulation reward by naloxone was investigated. Rats with bipolar electrodes implanted in either the median forebrain bundle (MFB) or the ventral tegmental area (VTA) were trained on a rate-independent threshold procedure. Effective threshold lowering doses of cocaine (10-15 mg/kg i.p.) were determined for each subject. A moderate dose of naloxone (4 mg/kg i.p.) effectively blocked the threshold lowering action of the cocaine. Lower (2 mg/kg) and higher (8 mg/kg) doses of naloxone attenuated but did not completely block the cocaine effect. These results provide further evidence for a catecholamine/endogenous opioid interaction in central reward.     

Angiotensin-converting enzyme inhibitory and antihypertensive activities of pivalopril (RHC 3659-(S))

Pivalopril (RHC 3659-(S); (S)-N-cyclopentyl-N-(2-methyl-3-pivaloylthiopropionyl) glycine) is a new compound with a hindered sulfur group that has been compared to captopril for oral angiotensin-converting enzyme (ACE) inhibition in rats and dogs and antihypertensive activity in rats. In separate groups of conscious normotensive rats, pivalopril (0.03-1.0 mg/kg, orally [p.o.]) produced a dose-related antagonism of angiotensin I (AngI)-induced pressor effects. The ED50 for pivalopril and captopril was 0.1 mg/kg. In conscious normotensive dogs, pivalopril (incremental doses of 0.01-1.0 mg/kg, p.o.) produced a dose-related antagonism of AngI pressor effects. The ED50 was 0.17 mg/kg for pivalopril and 0.06 mg/kg for captopril. At equieffective doses the two compounds had similar durations of action. In sodium-deficient, conscious spontaneously hypertensive rats (SHR), pivalopril (1-100 mg/kg, p.o.) produced a dose-related reduction in mean arterial pressure. The potency and duration were similar to those of captopril. In the sodium-replete SHR, 5 days of oral dosing with pivalopril, 100 mg/(kg . day), decreased mean arterial pressure more effectively than captopril, 100 mg/(kg . day). No tolerance developed to the antihypertensive effect of either drug. It is concluded that pivalopril is a potent, orally effective ACE inhibitor and antihypertensive agent.     

Quaternary narcotic antagonists' relative ability to prevent antinociception and gastrointestinal transit inhibition in morphine-treated rats as an index of peripheral selectivity

Single doses of naloxone (0.025 to 0.5 mg/kg) or of one of four quaternary narcotic antagonists (i.e. nalorphine allobromide, nalorphine methobromide, naloxone methobromide or naltrexone methobromide, 1 to 60 mg/kg) were given s.c. to rats before morphine, 5 mg/kg i.v. In the absence of antagonists morphine reduced G.I. transit of a charcoal meal to about 15% of drug-free controls and consistently delayed nociceptive reactions (55°C hot plate) in all animals. Doses of antagonists slightly reducing morphine antinociception (centrally effective = A) and restoring G.I. transit to about 50% of drug-free rats (peripherally effective = B) were estimated. The A:B ratio, indicating peripheral selectivity, was at least 8 for any of the quaternary antagonists given 10 min before morphine, but prolonging this interval may have resulted in a lower figure (i.e. less peripheral selectivity) because of reduced A and increased B. This was definitely so for naltrexone methobromide (A:B, > 60 at 10 min, about 1 at 80 min) and was not apparent for nalorphine methobromide according to available data, which for nalorphine allobromide and to a lesser extent for naloxone methobromide showed only an increase in B at intervals longer than 10 min. Both morphine-induced antinociception and inhibition of G.I. transit were reduced by naloxone at the lower doses tested and were fully prevented at the higher. These findings indicate that, unlike naloxone, the investigated quaternary narcotic antagonists are interesting prototype drugs for selective blockade of opiate receptors outside the CNS, although certain critical aspects, possibly biological N-dealkylation to the corresponding tertiary antagonists, condition peripheral selectivity.     

Antinociceptive effect induced by intraperitoneal administration of vitamin K2 (menatetrenone) in ICR mice

The antinociceptive effect of vitamin K2 (menatetrenone) in mice was examined using tail-flick and formalin test. Menatetrenone at doses of 10, 50 and 100 mg/kg, i.p. produced a dose-dependent and significant inhibition of the tail-flick response in mice. Menatetrenone (50 and 100 mg/kg, i.p.) had no significant effect on the duration of the first phase of the formalin-induced flinching. However, menatetrenone (100 mg/kg, i.p.) significantly inhibited the second phase of the formalin-induced flinching. I.p. administration of menatetrenone (100 mg/kg) significantly reduced the duration of nociceptive responses induced by i.t. injection of bradykinin, but not of substance P, prostaglandin E2 or N-methyl-D-aspartate (NMDA). These present data suggest that i.p. pretreatment with menatetrenone produced dose-dependent antinociceptive effect in mice. This effect may be, at least in part, mediated by the inhibition of bradykinin dependent nociceptive transmission in the spinal cord.     

Attenuation by naloxone of the pressor effects of angiotensin II in conscious cynomolgus monkeys

The effects of naloxone and morphine on mean arterial blood pressure (MBP) and heart rate (HR) responses to angiotensin II (AII) were studied in conscious cynomolgus monkeys. Graded doses of AII (0.3, 1 and 3 micrograms/min for 8-10 min) were infused i.v. 20 min apart, preceded by an i.v. injection of either naloxone (1, 3 or 10 mg/kg), morphine (0.3, 1 or 3 mg/kg) or saline. Pretreatment with naloxone (10 mg/kg) attenuated the pressor response to AII (0.3 or 1 microgram/min) by 25-50% but did not alter similar pressor responses to phenylephrine. Pretreatment with morphine had little or no effect on MBP or HR responses to AII.     

Dual dose-related action of peripherally administered morphine on cold-stimulated thyrotropin secretion in male rats

Cold-induced increase of thyrotropin (TSH) release was found to be inhibited after 10 or 20 mg/kg morphine sulfate (MO) injected intraperitoneally 30 min before the transfer of adult male rats from 30 to 4 degrees C for 60 min (i.e. 90 min before sacrifice). In contrast, lower doses of MO such as 2.5 and 5 mg/kg were found to stimulate the cold-induced TSH release under the same conditions. Such a cold-induced TSH release stimulated by lower doses of MO was found to be inhibited by intraperitoneal injection of 2 or 4 mg/kg naloxone (NX) 30 min before MO injection (i.e. 120 min before sacrifice) in a dose-dependent manner, while the same doses of NX were without effect on the levels of TSH after higher doses of MO. It is suggested that these effects may depend on different sensitivities of various hypothalamic loci involved in mediating either a stimulation or inhibition of TSH release.     

A study of the actions of naloxone and morphine on gastric acid secretion and gastric mucosal damage in the rat

There exists a considerable controversy in the literature with regard to the effect of either opiate receptor blockade or that of morphine in different gastric and intestinal ulcer models in the rat. We performed experiments to evaluate the effects of naloxone and morphine on gastric acid secretion and gastric mucosal damage in different experimental models of gastric mucosal injury, namely in indomethacin-, HCl (0.6N)- and ethanol (96%)-models. We found that: 1) 10 mg/kg naloxone ip given twice, effectively protected gastric mucosa against indomethacin (30 mg/kg ip) and against the acid-dependent injury caused by 0.6 N HCl (1 mL ig), but not against the non acid-dependent injury caused by 96% ethanol (1 mL ig); 2) morphine (10 + 10 mg/kg ip) increased ulcers in the HCl-model, but had no effect in the two other models; 3) this ulcer-aggravating effect of morphine in the HCl-model was blocked by pretreatment of 2 mg/kg ip naloxone; and 4) both naloxone (5 + 5 and 10 + 10 mg/kg ip) significantly decreased gastric acid secretion in 1-h pylorus ligated rats. We conclude that: 1) naloxone dose-dependently protects against the indomethacin- and HCl-, but not against the ethanol-induced gastric mucosal damage; 2) morphine aggravates the HCl-induced ulcerogenesis; and 3) both opiod receptor agonist and antagonist decrease gastric acid secretion.     

Role of endogenous opiates and extracellular K+ accumulation in the inhibition of frog spinal reflexes by electrical skin stimulation

Electrical skin stimulation of the hind limb (10-100 Hz, 30 s-5 min) at the intensity which leads only to the excitation of low threshold afferents depressed (for 1-30 min) the flexor reflex evoked in spinal frogs by nociceptive stimuli. The inhibition, which lasted for longer than 5 min was blocked by naloxone. Short-term poststimulation effects were associated with an increase of extracellular K+ concentration (delta [K]e) and were not blocked by naloxone. Enkephalins or morphine applied to the spinal cord surface increased the threshold for flexor reflexes while naloxone decrease their threshold. The stimulation was followed by short-term hyperpolarization of primary afferents (PAH; 1-5 min) and by depression of dorsal root potentials (DPRs) which had a similar time course to the delta [K]e, and were not blocked by naloxone. This period was frequently followed by longlasting PAH and enhancement of DRPs (5-30 min), which were abolished by naloxone. Superfusion of the isolated spinal cord with opioids produced PAH and enhanced DRPs evoked by nociceptive stimuli, while naloxone or increase of [K] in Ringer solution depolarized primary afferents and depressed DRPs. It is suggested that the antinociceptive effects of electrical stimulation of low threshold cutaneous afferents in spinal frogs involves at least two mechanisms. The short-term effect may result from delta [K]e, especially at high stimulus strength and is equally effective against noxious and non-noxious stimuli. The longlasting effects selectively affecting nociceptive transmission appear to be produced by endogenous opioids.     

Analgesia induced by intrathecal injection of dynorphin B in the rat

A dose-dependent analgesic effect of intrathecally injected dynorphin B was observed in rats using the tail flick as nociceptive test. Intrathecal injection of 20 nmol of dynorphin B increased the tail flick latency by 90 +/- 23%, an effect that lasted about 90 min. For the same degree of analgesia, dynorphin B was 50% more potent than morphine on a molar basis. The analgesic effect of this dose of dynorphin B was partially blocked by 10 mg/kg, but not by 1 mg/kg, of subcutaneous naloxone, showing a relative resistance to naloxone reversal as compared with morphine analgesia. The analgesia produced by dynorphin B was unchanged in morphine-tolerant rats but was significantly decreased in rats tolerant to ethylketazocine. These results suggest that dynorphin B produces its potent analgesic effect by activation of kappa rather than mu opioid receptors in the rat spinal cord.     

Effects of (D-ala2, met5)-enkephalinamide and naloxone on ACTH and corticosterone secretion

An intravenous administration of (D-ala2, met5)-enkephalinamide (DALA) caused a significant elevation of plasma ACTH and corticosterone at 10 to 20 min after injection in unanesthetized freely moving rats. An intraperitoneal administration of cyproheptadine tended to reduce plasma ACTH and corticosterone levels at 60 min after injection, but it did not attenuate the DALA-induced ACTH and corticosterone elevation. A large dose of naloxone (1-10 mg/kg body weight) caused a significant elevation in plasma corticosterone, but naloxone at 10 mg/kg body weight reduced the basal ACTH level and DALA-induced ACTH elevation. When both DALA and naloxone were injected, the steroidogenic effect was attenuated. Neither DALA nor naloxone affected the basal ACTH release and CRF-induced ACTH stimulation in rat anterior pituitary cell cultures. These results suggest that DALA acts at the extra-hypophyseal level to stimulate ACTH and corticosterone and that the naloxone stimulatory effect on steroidogenesis acts on the adrenal gland or is mediated by stimulating corticosterone stimulating factors other than ACTH.     

Action of Electric Stimulation and Captopril in Nociception and 3,5,3′‐Triiodothyronine Secretion in Mice

Transcutaneous electric nerve stimulation (TENS) analgesic effect is produced by β‐endorphin release which interacts with captopril, a drug used for arterial hypertension treatment that affects thyroid hormone secretion, mainly 3,5,3′‐triiodothyronine (T3). To study a correlation between TENS (9 Hz × 30 min), captopril and T3, Mus musculus mice received nociceptive stimulation (writhe‐induced model) and were treated with captopril (1 mg/kg) and TENS and the T3 serum level was evaluated. As a result, T3 serum level rose slightly after TENS application and captopril separately but increased more after captopril alone. In addition, the antinociceptive effect produced by electric stimulation was enhanced by captopril with a high statistical significance (p < 0.001). Additionally, the TENS–captopril treatment increased T3 serum level to values 117.7% higher than control groups, reinforcing the supposed link between neuroelectric stimulation, captopril, and T3 secretion.     

Bremazocine induces antinociception, but prevents opioid-induced constipation and catatonia in rats and precipitates withdrawal in morphine-dependent rats

Some in vivo agonist and antagonist properties of the putative k-compound bremazocine were characterized in rats. Bremazocine, at doses from 0.015-32 mg/kg i.p., delayed nociceptive reaction on a 55 degrees C hot-plate with a dose-response curve not readily fitting a single straight line; this effect was antagonized by high doses of naloxone. In the same rats bremazocine did not delay the intestinal transit of a charcoal meal fed 5 min earlier and prevented morphine-induced constipation. This antagonism appeared to be opioid-specific and competitive, with apparent pA2 value 8.56. Catatonia induced by etorphine (0.004 mg/kg s.c.) and constipation induced by etorphine (0.004 mg/kg s.c.) and D-Ala2-D-Leu5-enkephalin (0.1 mg/kg i.p.) were completely antagonized by bremazocine (0.03-8 mg/kg i.p.). Antinociception induced by morphine (10 mg/kg i.v.) and etorphine (0.004 mg/kg s.c.) was only partly prevented. Naloxone (1 mg/kg) and bremazocine (0.015-1 mg/kg i.p.) precipitated a withdrawal syndrome, evaluated as jumping frequency, in rats rendered dependent to morphine. These data suggest the involvement of more than one opioid receptor population in bremazocine action in vivo.     

Influence of captopril on the in vitro and in vivo effects of leu- and met-enkephalins

Captopril (10(-6) g/ml) enhanced and prolonged the inhibitory effect of leu- and met-enkephalins on the contractions of the isolated guinea-pig ileum section induced by electrical stimulation. In mice, the drug (25 mg/kg, subcutaneously) increased the degree and duration of the analgetic effect of enkephalins. It is concluded that the analgetic effect of captopril is related to the influence on the activity of the endogenous antinociceptive system.     

Action of narcotic analgesics and antagonists on spinal units responding to natural stimulation in the cat.

Morphine and morphine-related agents were applied by microiontophoresis in the lumbar spinal cord of spinal cats to single units classified on the basis of their responses to natural cutaneous or proprioceptive stimulation. Opiate application had a current-dependent depressant effect on the ongoing activities of about one-third of the units tested. This effect was observed in laminae I and IV--VI, but only with units responding to noxious cutaneous stimuli: the nociceptive responses were themselves depressed. Excitatory and inhibitory responses to glutamate and gamma-aminobutyric acid, respectively, were also depressed. Intravenous administration of the opiates at doses reported to produce analgesia in the cat also depressed only units responding to noxious cutaneous stimuli, including their nociceptive responses. This depression could be reversed by either the iontophoretic application (100 nA) or the intravenous administration (0.1--0.8 mg/kg) of naloxone. These results are interpreted as further evidence that the analgesic effects of opiates are at least partly due to an action at the spinal level.     

Selective analgetic effects of angiotensin and bombesin during the action of dental and cutaneous nociceptive irritants

In non-anesthesized rabbits intraventricular injection of angiotensin II reduced the amplitude of somatosensory evoked potential to nociceptive tooth pulp, but not to nociceptive electrocutaneous stimulation. The same injection of bombesin induced the contrary analgetic effect. The systemic naloxone (0.1 mg/kg) injection didn't reverse the peptides analgetic effects. It's suggested that selective analgetic effects of angiotensin II and bombesin are determined by the presence of the specific different peptide mechanisms for nociception with the different pain genesis.     

Effects of morphine and naloxone administered to pregnant rats on the adrenal glands and testes of the offspring]

Relative testis and adrenal weights, testosterone and corticosterone levels in the blood were determined in 9-, 16-day and 2-month-old rats born to females injected with morphine (10 mg/kg/day), naloxone (10 mg/kg/day) or saline throughout the 15-18 days of gestation. Opioid receptors agonist morphine caused a long-lasting inhibition of the testes and activation of the adrenals. Saline injections to the females, that are known to be a stressor for them, also inhibited the testis of the neonatal offsprings. The block of the opioid receptors by the naloxone prevented the effect of prenatal stress on the testis, but inverted the negative correlation between the testes and the adrenals, that can be observed in the normal development.     

The effect of inhibitors of endogenous opioid degradation, bacitracin, bestatin, captopril, and D-phenylalanine, on digoxin-induced arrhythmias in guinea pigs

The purpose of this study was to investigate the effect of inhibition of endogenous opioid degradation on digitalis-induced arrhythmias, utilizing the inhibitors bacitracin, bestatin, captopril, and D-phenylalanine. Guinea pigs, anesthetized with pentobarbital, 50 mg/kg i.p., and breathing spontaneously received intracerebroventricular (i.c.v.) injection of bacitracin (6.8 mg/kg), bestatin (1 mg/kg), captopril (2 mg/kg), D-phenylalanine (1.2 mg/kg) or the diluent, saline. Digitalis arrhythmias were induced by a 50 micrograms/kg i.v. bolus of digoxin followed by 500 micrograms.kg-1.h-1 i.v. Bacitracin and bestatin, but not captopril or D-phenylalanine, significantly (p less than 0.05) altered the relationship between the digoxin dose and the first occurrence of arrhythmias, i.e., digoxin-induced ventricular arrhythmias became manifest at lower digoxin doses. The mean digoxin dose and ED50s, at which arrhythmias first occurred, were significantly (p less than 0.05) reduced by bacitracin and bestatin. The findings were similar for fatal arrhythmias, although D-phenylalanine appeared to decrease the digoxin dose at the development of fatal arrhythmias. The opioid antagonist naloxone, in a 50 micrograms/kg bolus and 50 micrograms.kg-1.h-1 i.c.v., completely prevented these effects of bacitracin and reduced the effect of bestatin. The relationship to arrhythmias could not be ascribed to an effect on blood pressure, as the blood pressure response to digoxin was the same in bestatin, D-phenylalanine, and control groups. To examine whether systemic administration of an inhibitor of opioid degradation had similar effects, a second protocol was selected with systemic administration of bacitracin because it altered the dose effect relationship after i.c.v. administration and systemic concentrations could be readily attained. Bacitracin, in a 13.5 mg/kg i.v. bolus and 135 mg.kg-1.h-1 i.v., was followed by 100 micrograms/kg digoxin i.v. every 15 min.(ABSTRACT TRUNCATED AT 250 WORDS)     

Differential role of opioid receptors in tibial nerve inhibition of nociceptive and nonnociceptive bladder reflexes in cats

Naloxone (an opioid receptor antagonist) was used to examine the role of opioid mechanisms in bladder reflexes and in somatic afferent inhibition of these reflexes by tibial nerve stimulation (TNS). Experiments were conducted in α-chloralose-anesthetized cats when the bladder was infused with saline or 0.25% acetic acid (AA). The bladder volume was measured at the first large-amplitude (>30 cmH(2)O) contraction during a cystometrogram and termed "estimated bladder capacity" (EBC). AA irritated the bladder, induced bladder overactivity, and significantly (P < 0.0001) reduced EBC to 14.3 ± 1.9% of the saline control. TNS (5 Hz, 0.2 ms) at 4 and 8 times the threshold (T) intensity for inducing an observable toe movement suppressed AA-induced bladder overactivity and significantly increased EBC to 41.5 ± 9.9% (4T, P < 0.05) and 46.1 ± 7.9% (8T, P < 0.01) of the saline control. Naloxone (1 mg/kg iv) completely eliminated TNS inhibition of bladder overactivity. Naloxone (0.001-1 mg/kg iv) did not change EBC during AA irritation. However, during saline infusion naloxone (1 mg/kg iv) significantly (P < 0.01) reduced EBC to 66.5 ± 8.1% of the control EBC. During saline infusion, TNS induced an acute increase in EBC and an increase that persisted following the stimulation. Naloxone (1 mg/kg) did not alter either type of inhibition. However, naloxone administered during the poststimulation inhibition decreased EBC. These results indicate that opioid receptors have different roles in modulation of nociceptive and nonnociceptive bladder reflexes and in somatic afferent inhibition of these reflexes, raising the possibility that opioid receptors may be a target for pharmacological treatment of lower urinary tract disorders.