Analgesia in phasic and tonic pain tests in a pharmacological model of autotomy.

Self-mutilation or self-injurious behaviour is a well known behavioural disorder in humans. The proposition that this behaviour in animals is a response to chronic pain of peripheral nerve injury has been met with controversy. In the present study a pharmacological model, which produces no sensory or motor loss was used to study how autotomy is related to pain. In a group of rats autotomy was induced by amphetamine in phenoxybenzamine and reserpine treated animals. The pain tests, both phasic and tonic were then performed. The results of this study showed that a total analgesia was produced in both phasic and tonic pain tests, in animals that exhibited autotomy. Injection of naloxone in these animals prevented autotomy. A correlation between autotomy and no pain is suggested in this pharmacological model of autotomy.

Influence of moderate cooling (37§C-25§C) on the reactivity of isolated rat tail artery

The aim of the investigation was to examine the effects of cooling on the tail artery regarding the scarceness of such studies in spite of the essential thermoregulatory role played by this vessel. Segments of the proximal portion were suspended isometrically in medium containig 1.25 mM Ca. Lowering the temperature to 25 degrees Celsius increased the sensitivity and maximum strength of the adrenaline concentration-effect curves. These changes were reversed by warming to 37 degrees Celsius. Cocaine attenuated the increase of sensitivity without changing the increase of the maximum response. Either the sensitivity and strength of the responses to phenylephrine and serotomin were increased by cooling. Clonidine evoked weak contractions in 18 out of 38 experiments. After cooling, the responses persisted only in 7 arteries and the strength was almost halved. Responses to field eletric stimulation at 25 degrees Celsius exhibited a pronounced increase of strength and a small increase of sensitivity. -log Kb for prazosin against adrenaline was encreased by cooling (8.7 and 9.1 at 37 degrees Celsius and 25 degrees Celsius C, P<0.01). After partial receptor inactivation using phenoxybenzamine, the dissociation-constant (KA) indicated a moderate affinity for phenylephrine that was not changed by cooling (4.1 and 4.2 x 10(-6) at 37 degrees Celsius respectively). Receptor reserve and occupancy at EC(50) also remained unchanged at 25 degrees Celsius. It can be concluded that: 1) cooling increases the tail artery reactivity, partly as a consequence of the inhibition of adrenergic neuronal uptake; 2) responsiveness to alpha 2-agonists is not in volved in the effects of cooling whereas the role of alpha 1-adrenoceptor could not be properly clarified; 3) cooling may facilitate some steps of the contractile activation beyond the agonist-receptor interaction.

Antinociception induced by stimulating amygdaloid nuclei in rats: changes produced by systemically administered antagonists

The antinociceptive effects of stimulating the medial (ME) and central (CE) nuclei of the amygdala in rats were evaluated by the changes in the latency for the tail withdrawal reflex to noxious heating of the skin. A 30-s period of sine-wave stimulation of the ME or CE produced a significant and short increase in the duration of tail flick latency. A 15-s period of stimulation was ineffective. Repeated stimulation of these nuclei at 48-h intervals produced progressively smaller effects. The antinociception evoked from the ME was significantly reduced by the previous systemic administration of naloxone, methysergide, atropine, phenoxybenzamine, and propranolol, but not by mecamylamine, all given at the dose of 1.0 mg/kg. Previous systemic administration of naloxone, atropine, and propranolol, but not methysergide, phenoxy-benzamine, or mecamylamine, was effective against the effects of stimulating the CE. We conclude that the antinociceptive effects of stimulating the ME involve at least opioid, serotonergic, adrenergic, and muscarinic cholinergic descending mechanisms. The effects of stimulating the CE involve at least opioid, beta-adrenergic, and muscarinic cholinergic descending mechanisms.

Antinociceptive effects of stimulation of discrete sites in the rat hypothalamus: evidence for the participation of the lateral hypothalamus area in descending pain suppression mechanisms

The sites in the rat hypothalamus where microinjection of morphine 5 mug/0.5 mul) or electrical stimulation depresses the tail withdrawal reflex to noxious heating of the skin were examined. Among other hypothalamic sites found to be sensitive to morphine or to an electrical stimulus, the posterior part of the lateral hypothalamic area (LHA) was the only portion of the hypothalamus that was strongly sensitive to both manipulations. A 15-sec period of 35-muA sine-wave stimulation of the LHA significantly increased the latency of the tail reflex for periods up to 30 min. The effects of intraperitoneal administration of antagonists to opioids (naloxone), 5-hydroxytryptamine (methysergide), noradrenaline (phenoxybenzarnine), dopamine (haloperidol and acetylcholine (atropine and mecamylamine) on the antinociceptive effects of LHA stimulation were also examined. Naloxone, methysergide, and atropine (all given at doses of 0.5 and 1.0 mg/kg attenuated the effects of LHA stimulation in a dose-dependent manner. Phenoxybenzamine, but not haloperidol (both at the dose of 1.0 mg/kg), was also effective but dose-dependent curves could not be constructed. Mecamylamine (1.0 mg/kg) reduced the duration but no the peak effect of stimulating the LHA. We conclude that antagonism at the level of opioid, serotonergic, adrenergic, and muscarinic cholinergic receptors, but not dopamine or nicotinic cholinergic receptors reduces the antinociceptive effects of LHA stimulation. This may imply that antinociception evoked from the LHA depends on the activation of descending pathways that relay in the mesencephalic periaqueductal gray matter and then in the nucleus raphe magnus and/or nucleus reticularis paragigantocellularis.

Vascular effects of ipsapirone are related with subtypes of alpha 1-adrenergic receptors

The aim of this study was to provide further evidence about the participation of Ó1-adrenoceptors in the vascular responses elicited by impsapirone. This 5-HT 1A agonist displayed vasodilator activity only when aortic rings were precontracted by Ó-adrenergic compounds. The relaxant effect was particulary evident when rings were precontracted with methoxamine (selective Ó1A-adrenergic agonist).On the other hand, ipsapirone but chloroethylclonidine (selective Ó1B-adrenergic antagonist), clearly displaced norepinephrine and methoxaminevasocontractile concentration-response curves to the right. Fanally, ipsapirone protected the Ó-adrenoceptors from the irreversible blockade provoked by phenoxybenzamine, as judged by thenorepinephrine contraction and stimulated phosphatidylinositil labeling. Accordingly the relaxant effect elicited by ipsapirone in aortic rings precontracted with Ó-adrenergic agonists and the protective action against blockade by phenoxybenzamine shown by this agent are proof of its ability to occupy Ó1-adrenoceptors. Specifically, Ó1A-adrenergic receptors seem to be involved in ipsapirone vascular effects, since this agent selectively relaxed aortic preparation precontracted with methoxamine and unlike chloroethylclonidine, clearly inhibited the contractile effect of this agonist. In summary, the present findings can be explained by accepting that ipsapirone may act as an antagonist at Ó1A-adrenoceptors

Efeitos do propranolol e da fenoxibenzimina sobre a resposta febril induzida pelo lipopolissacarídeo de E. coli, em coelhos / Effects of propranolol and phenoxibenzamine on the febrile response induced in rabbits by lipopolysaccharide from E. coli

Drogas bloqueadoras de receptores Alfa e Beta adrenérgicos, como a fenoxibenzamina e o propranolol, produziram reduçäo estatisticamente significante da resposta febril induzida pelo lipopolissacarídeo de E. coli (LPS) em coelhos. Os presentes resultados sugerem que receptores Alfa e Beta adrenérgicos poderäo estar envolvidos nessa resposta febril

Norepinephrine: stimulated activity of hypothalamic adenylate cyclase varies throughout the estrous cycle of the female rat

The activity of hypothalamic adenylate cyclase was studied throughout the estrous cycle of the female rat. The activity of the enzyme was determined in particulate fractions obtained from hypothalami of rats killed at 10.00 h and 16.00 h of the 4-day estrous cycle. The activity was assayed in the presence of norepinephrine (10(-8) to 10(-3) M) by the capacity to produce adenosine 3',5' cyclic monophosphate. The basal activity of adenylate cyclase was higher in the morning of estrus than at any other time during the cycle. Norepinephrine-stimulated adenylate cyclase activity, as assessed by the apparent affinity (Kd) and apparent maximum effect, varied during the cycle, showing highest affinity, lowest Kd, in the afternoon of proestrus. The highest level of apparent maximum effect was also found in the afternoon of proestrus declining on diestrous day 2, diestrous day 1 and estrus. The norepinephrine stimulated activity was significantly inhibited by phenoxybenzamine, an alpha-blocker, in the morning of diestrus day 1, whereas on the day of diestrus day 2 and proestrus it was inhibited by the beta-adrenoblocker, propranolol. A similar degree of inhibition by alpha- and beta-blockers was observed in the morning of estrus. These results indicate that the hypothalamic adenylate cyclase coupled to adrenergic receptors shows dynamic changes throughout the estrous cycle

Role of opioid receptors in self-aggression in rats.

Self-aggression is a behavioural disorder in which an individual damages its own body parts by intense biting or scratching. Self aggression has been reported in human patients in Lesch-Nyhan syndrome and in cases of schizophrenia, depression, and congenital analgesia. In human patients as well as in experimental animals some kind of dysesthesia of the part of the body that is mutilated has been suggested. This study was conducted to find out the underlying pain mechanisms in self-aggressive behaviour arising out of stereotypy. The study was performed in 40 adult male rats. In all these animals, self-aggression was produced as part of amphetamine induced stereotyped behaviour. A predetermined scale was used for quantifying this behaviour. Reserpine and phenoxybenzamine pretreatment led to an increase in the incidence of self-aggression. Naloxone administration in reserpine pretreated animals led to a further significant increase in the incidence of self biting as compared to controls. From these studies it appears that self-aggressive behaviour may be associated with increased pain sensation.

Central hyperthermic effect of arsenic in rabbits.

Hyperthermic effect of arsenic was investigated in rabbits. Injections of arsenic trioxide (0.0001 to 0.1 micrograms) into a lateral cerebral ventricle of the rabbit evoked a dose-dependent hyperthermia, respiratory stimulation and peripheral vasodilatation. Heat loss through respiratory stimulation and peripheral vasodilatation appeared responsible for the long latent period and the slight hypothermia sometimes obtained during this period as these effects followed the same time course. These effects were centrally mediated as demonstrated by the lack of efficacy of the same doses by the intravenous route. The hyperthermic effect of arsenic was antagonized by the sulphydryl donator, dimercaprol, the a-adrenoceptor blocking agent-phenoxybenzamine and the PG-synthesis inhibitor-aspirin. Multiple sites, for antagonistic effects of these substances can be explained by the action of arsenic in inactivating sulphydryl containing enzymes which are many and catalyze diverse biochemical reactions.

Involvement of adrenergic & cholinergic mechanisms in analgesia electrically induced from pretectal nucleus of rat.

Analgesia induced by pretectal stimulation in rat was analysed using suitable antagonists. Mild electrical stimulation of sites in the pretectal nucleus (PTN) caused analgesia of long duration, without signs of aversion and unassociated with motor deficit. Pretreatment of animals with ip atropine sulphate (1 mg/kg), phenoxybenzamine (5 mg/kg), sotalol (2 mg/kg) and haloperidol (1 mg/kg) but not with saline, markedly reduced the antinociceptive response to PTN stimulation. Mild PTN stimulation thus seems to induce potent and long lasting analgesia in rats probably involving multisynaptic antinociceptive pathway(s).

Effect of monoamine antagonists on pretectal evoked analgesia in rat.

Mild and brief electrical stimulation of sites in the pretectal nucleus of rat produced analgesia (SPA) of long duration without significant aversion. Intracerebroventricular (icv) administration of 5-HT receptor antagonists methysergide (50 micrograms) and ketanserin (50 micrograms) and the dopaminergic antagonist haloperidol (50 micrograms) had no significant effect on pretectal SPA, but alpha and beta adrenoceptor antagonists phenoxybenzamine (50 micrograms) and sotalol (50 micrograms) on icv injection significantly antagonised the pretectal SPA. The results suggest that pretectal SPA involves activation of central adrenoceptors.

Catecholaminergic influences on induced hippocampal paroxysmal activity in rats

Catecolaminas cerebrales (noradrenalina y dopamina), parecen suprimir ciertas formas de actividad epiléptica. En este trabajo relatamos las influencias catecolaminérgicas sobre actividad paroxística hipocampal inducida en ratas por medio de estimulación eléctrica hipocampal a través de electrodos implantados estereoáxicamente. El experimento incluye: (1) Inyección sistémica de clonidina (0.10 mg/kg); fenoxibenzamina (10 mg/kg); propranolol (10 mg/kg); apomorfina (1 mg/kg) y haloperidol (1 mg/kg) y (2) lesión electrolítica del locus coeruleus ipsilateral al hipocampo estimulado. El grupo clonidina presenta una gran reducción, en tanto que los animales que recibieron fenoxibenzamina presentaron un significativo aumento en la actividad convulsiva electrográfica. Propranolol produjo sólo una reducción pasajera de actividad epiléptica. No hemos observado ningún cambio significativo en las descargas epilépticas que siguen a la inyección de apomorfina y haloperidol. Lesión electrolítica del locus coeruleus induce un significativo aumento de la actividad epileptiforme. Los resultados aquí presentados apoyan la idea que el sistema noradrenérgico, pero no el dopaminérgico, puede ejercer un efecto inhibitorio tónico sobre la actividad epiléptica hipocampal

Effect of propranolol and phenoxybenzamine on muscle strength and physical endurance, and on exercise-induced changes in muscle glycogen and blood lactic acid levels in rats.

Propranolol and phenoxybenzamine (PBZ) had no major effect on swimming-endurance performance and skeletal muscle pulling-strength in rats. Propranolol, like exercise itself diminished the resting skeletal muscle glycogen (SMG) content, but the drug did not lower the resting blood lactic acid (BLA) levels. Propranolol significantly antagonised the 25-min exercise-induced BLA elevation, indicating that lactacidaemia is possibly a beta-receptor response. However, propranolol did not exhibit an overall beneficial effect on swimming endurance. PBZ had a negligible effect on maximal swimming time (MST) and had no major effects on the SMG content and BLA levels.

Adrenergic receptors in the hypothalamus concerned with control of arterial blood pressure: elicited by electrical and chemical stimulation.

The study was made with the help of a chemitrode placed in various areas of the hypothalamus by the stereotaxic technique, for electrical and chemical stimulation (noradrenaline or isoprenaline) before and after microinjection of respective blockers (phenoxybenzamine or practalol). The results indicated the presence of both alpha and beta-adrenoreceptors in the anterior and dorsomedial hypothalamus producing a depressor response, and, the presence of alpha adrenoreceptors in the posterior and lateral hypothalamus producing a pressor response.

Studies on rectal temperature of rats in relation to seasonal air temperature and morphine administration.

The present findings demonstrate that seasonal air temperature does not only influence the basal core temperature of rats, but also modifies the physiological/pharmacological actions of drugs. Thus, at low ambient temperature, intracerebroventricular on intraperitoneal administration of morphine produces mainly hypothermia followed by a secondary rise in rectal temperature. On the other hand, at high ambient temperature, the drug produces hyperthermia only. The hypothermic response at low ambient temperature is abolished by pretreatment of rats with 6-hydroxydopamine but not with phenoxybenzamine administration. This suggests that catecholamine pathway in the central nervous system is involved in morphine induced hypothermic response. Further, the role of cholinergic neurons in such response is also indicated.