Estrogen regulates adrenal medullary function producing sexual dimorphism in nociceptive threshold and beta-adrenergic receptor-mediated hyperalgesia in the rat

Epinephrine produces sexually dimorphic beta(2)-adrenergic receptor-mediated mechanical hyperalgesia, with male rats exhibiting greater hyperalgesia. Because female rats have higher plasma epinephrine levels, and beta-adrenergic receptor sensitivity is affected by chronic exposure to agonists, we tested the hypothesis that this sexual dimorphism is due to epinephrine-induced desensitization of beta(2)-adrenergic receptors. Following gonadectomy, epinephrine hyperalgesia, as measured by the Randall-Selitto paw-withdrawal test, was unchanged in male rats while in females it was increased. Prepubertal male and female rats do not demonstrate sexual dimorphism in either plasma epinephrine level or epinephrine-induced hyperalgesia. Adrenal medullectomy and adrenal denervation both significantly enhanced epinephrine hyperalgesia, but only in females. In contrast, the sexually dimorphic hyperalgesia induced by prostaglandin E(2), another agent that acts directly to sensitize primary afferent nociceptors, was not enhanced by adrenal medullectomy or denervation. Chronic administration of epinephrine in male rats, to produce plasma levels similar to those of gonad-intact females, significantly attenuated epinephrine-induced hyperalgesia, making it similar to that in females. These results strongly support the suggestion that estrogen regulates plasma epinephrine in female rats and differential sensitivity to beta(2)-adrenergic agonists accounts for the sexual dimorphism in epinephrine-induced hyperalgesia. Unexpectedly, regulation of adrenal medullary function by estrogen was also found to modulate baseline nociceptive threshold such that females had a lower nociceptive threshold.     

Formalin attenuates the stress-induced increase in plasma epinephrine levels

Subcutaneous (s.c.) injection of formalin into rats is frequently used as a painful stressor that produces a three-phase nociceptive response. We have shown previously that s.c. administered formalin (0.2 ml of 4% solution per 100 g body weight) unexpectedly attenuated the increase of plasma epinephrine levels in rats exposed to exteroceptive stressors (handling, immobilisation). To clarify the mechanism(s) responsible for this phenomenon, the effect of formalin applications on epinephrine plasma levels was investigated in various experimental conditions. Subcutaneous application of formalin combined with exposures of animals to an interoceptive stressor, insulin-induced hypoglycaemia, significantly attenuated the stress-induced increase in plasma epinephrine levels, whereas plasma norepinephrine levels remained highly elevated. Moreover, administration of formalin to unstressed animals also manifested signs of an attenuated epinephrine secretion. Interestingly, intraperitoneal administration of formalin did not reduce the elevated levels of plasma epinephrine. We suggest that formalin attenuates epinephrine secretion from the adrenal medulla most probably via irritation of s.c. somatosensory receptors. We hypothesise that the irritation of the primary sensory afferents fibres might reduce the activity of the sympathetic preganglionic neurones innervating adrenal medullary chromaffin cells. Further investigations are required to establish whether the observed reduction of epinephrine secretion from the adrenal medulla is controlled by either spinal or supraspinal neuronal circuits.     

Modulation of bradykinin‐induced mechanical hyperalgesia in the rat by activity in abdominal vagal afferents

Bradykinin-induced plasma extravasation and mechanical hyperalgesia are sympathetic-dependent components of inflammation. Noxious stimulation has been found to inhibit bradykinin-induced plasma extravasation by activating the hypothalamo-pituitary-adrenal axis. The sensitivity of this nociceptive-neuroendocrine feedback control of inflammation is modulated by activity in subdiaphragmatic vagal afferents. In the present study, we tested the hypothesis that activity in the subdiaphragmatic vagus also modifies bradykinin-induced mechanical hyperalgesia in the rat, using the Randall–Selitto method. Following subdiaphragmatic vagotomy, the baseline paw-withdrawal threshold to mechanical stimulation decreased and bradykinin-induced mechanical hyperalgesia was enhanced. Mechanical hyperalgesia produced by prostaglandin E₂, a direct-acting hyperalgesic agent, was not significantly affected by vagotomy. The effect of subdiaphragmatic vagotomy on bradykinin-induced hyperalgesia, but not on baseline paw-withdrawal threshold, was mimicked by coeliac branch vagotomy. Indomethacin blocked the hyperalgesia in normal rats, but not in vagotomized rats, suggesting that bradykinin-induced hyperalgesia in normal rats is mediated by prostaglandins, whose role was unexpectedly diminished after vagotomy. Bradykinin-induced hyperalgesia in normal rats was abolished by lumbar sympathectomy but not by sympathetic decentralization (cutting the preganglionic axons). In rats that were both vagotomized and sympathectomized, hyperalgesia induced by low-dose bradykinin was no longer present. These results demonstrate that vagotomy induces a decrease in baseline mechanical paw-withdrawal threshold and an enhancement of bradykinin-induced mechanical hyperalgesia and suggest that these phenomena are generated by actions in peripheral tissues.     

Evidence for involvement of an adrenal catecholamine in the β-adrenergic inhibition of oxytocin release in lactating rats

Adrenergic systems exert dual control over the release of oxytocin (OT) in rats, with stimulation of α-adrenergic receptors exciting, and stimulation of β-adrenergic receptors inhibiting, release of this neurohormone. Because suckling stimulation also releases epinephrine from the adrenal medulla, the present experiments tested whether catecholamines of adrenal origin may participate in the adrenergic regulation of OT release during lactation. In two independent experiments, adrenal demedullation of rats in midlactation did not alter the basal plasma levels of OT, but makedly enhanced the suckling-induced release of OT, suggesting an inhibitory action of an adrenal catecholamine. The OT release induced by suckling in both sham-operated and adrenal demedullated rats was prevented by stimulation of β-adrenergic receptors with isoproterenol. Conversely, blockade of β-adrenergic receptors with propranolol prevented the inhibitory effects of isoproterenol, and when given alone, mimicked the effects of demedullation to enhance suckling-induced OT release. Stimulation of peripheral α-adrenergic receptors with phenylephrine did not affect either basal or suckling-induced OT release, but blockade of α-adrenergic receptors with phentolamine also completely prevented the release of OT by suckling. These data support the concept that stimulation of β-adrenergic receptors inhibits OT secretion, and further suggest that this may be due, at least in part, to an action of an adrenal catecholamine, which may act centrally and/or directly on the neurohypophysis. The present results also provide further evidence that activation of central, but not peripheral, α-adrenergic mehcanisms is necessary for suckling-induced OT release.     

Beta-endorphin-induced increases in plasma epinephrine, norepinephrine and dopamine in rats: inhibition of adrenomedullary response by intracerebral somatostatin

Synthetic human beta-endorphin, 7.25 nmol intracisternally, in unanesthetized, freely moving, chronically cannulated, adult male rats increased plasma concentrations of all 3 catecholamines: epinephrine, norepinephrine and dopamine, for the 2 h period studied. Blockade of these endorphin effects by the prior systemic administration of naloxone supports mediation of the effects at opioid receptors. Acute systemic administration of guanethidine, which decreases norepinephrine release induced by sympathetic nerve stimulation, blunted the plasma norepinephrine response to intracerebral beta-endorphin. Thus, it seems likely that in addition to secretion by adrenal medulla a considerable portion of the beta-endorphin-induced increase in norepinephrine is derived from sympathetic nerve endings. Simultaneous intracisternal administration of another neuropeptide, somatostatin, together with beta-endorphin markedly inhibited the plasma epinephrine response to beta-endorphin, while decreasing the dopamine and norepinephrine responses to a much lesser degree. The dats suggest that beta-endorphin stimulates central sympathetic outflow to both adrenal medulla and sympathetic nerve endings, and further that somatostatin inhibits the effect of endorphin to stimulate outflow to adrenal medulla but does not affect outflow to sympathetic nerve endings.     

β-Adrenoceptor blockade spares chemoreceptor responsiveness to hypoxia

The effect of β-adrenoceptor blockade on the carotid body chemoreceptor response to hypoxia was assessed in anesthetized and paralyzed cats. Propranolol, atenolol and ICI 118,551 each abolished the enhancement of chemoreceptor activity produced by i.v. infusion of exogenous isoproterenol; however the blocking durgs did not significantly diminish the increase in chemoreceptor neural discharge induced by hypoxia. These results do not support the hypothesis that β-adrenergic receptors play an essential role in the chemoreceptor response to oxygen deprivation.     

Modulation of hypoglycemia-induced increases in plasma epinephrine by estrogen in the female rat

Clinical studies have demonstrated that estrogen replacement therapy suppresses stress-induced increases in plasma catecholamines. The present study determined whether normal circulating levels of estrogen can modulate hypoglycemia-induced increases in plasma epinephrine (EPI). In anesthetized female rats, insulin-induced hypoglycemia (0.25 U/kg) increased plasma EPI concentration to a significantly greater extent in 14-day ovariectomized (OVEX) rats compared to that in sham-operated controls. In 17beta-estradiol (E2)-replaced OVEX rats, the hypoglycemia-induced rise in plasma EPI was reduced significantly when compared to that in vehicle-replaced OVEX rats. OVEX and E2 replacement had no effect on tyrosine hydroxylase or phenylethanolamine N-methyltransferase mRNA levels in the adrenal medulla. In isolated adrenal medullary chromaffin cells, agonist-induced increases in intracellular Ca2+ were unaffected by 48-hr exposure to 10 nM E2. In contrast, acute (3-min) exposure to micromolar concentrations of E2 dose-dependently and reversibly inhibited agonist-induced Ca2+ transients. In addition, in OVEX rats, a constant infusion of E2 significantly reduced the insulin-induced increase in plasma EPI concentration compared to that in vehicle-infused controls. These data demonstrate that physiologic levels of circulating E2 can modulate hypoglycemia-induced increases in plasma EPI. This effect seems independent of steroid influence on adrenal medullary secretion or biosynthesis. In contrast, acute exposure to high levels of E2 can also suppress hypoglycemia-induced increases in plasma epinephrine, due at least in part to inhibition of stimulus-secretion coupling.     

Adrenal medullary responses to insulin-induced hypoglycaemia in the young rat. Influence of thyroid hormones

The adrenal medulla of normal, hypothyroid and hyperthyroid young rats was stimulated by insulin-induced hypoglycaemia. In normal rats, insulin-induced adrenal epinephrine secretion increases during the first 10 days of post-natal life. Hypothyroidism retards the development of adrenal response; hyperthyroidism facilitates the development of this response. At 14 days, when insulin-induced adrenal epinephrine depletion is the same for all groups, the recovery of adrenal catecholamines stores after depletion is linear and takes less than 48 h. Recovery rate is slightly slower for hyperthyroid rats than for either hypothyroid or control rats at 14 days. Following epinephrine depletion, adrenal tyrosine hydroxylase (TH) and dopamine-beta-hydroxylase (DBH) activities are increased for a few days in the control rats, corresponding to a transsynaptic induction. Hypothyroidism impairs TH induction and completely suppresses DBH induction; hyperthyroidism impairs TH induction, but has no effect on DBH induction. These data show that the various processes related to CA synthesis, in the adrenal medulla of the developing rat, are controlled in different ways by the thyroid hormones.     

Platelet alpha 2-adrenergic receptors in schizophrenic patients before and after phenothiazine treatment

The specific binding to isolated platelet membranes of 3H-clonidine, an alpha 2-adrenergic receptor partial agonist, and 3H-yohimbine, an alpha 2-adrenergic receptor antagonist, was measured in male, drug-free schizophrenic patients. The maximum number of binding sites (Bmax) for 3H-yohimbine was significantly lower in these patients than in normal subjects. Treatment with chlorpromazine (CPZ) for 2 weeks further decreased the Bmax for both ligands. Plasma catecholamine levels were determined before and after treatment. Before treatment, levels of dopamine and norepinephrine (NE) were within a normal range, while epinephrine (E) levels were significantly elevated. CPZ treatment significantly increased plasma NE levels, but decreased E levels to a normal range. These observations suggest that schizophrenia might be associated with abnormal noradrenergic function that is reflected by a decreased number of platelet alpha 2-adrenergic receptors.     

Alpha-adrenergic receptor agonists, but not antagonists, alter the tail-flick latency when microinjected into the rostral ventromedial medulla of the lightly anesthetized rat

The present experiments, part of an ongoing study designed to characterise the role of norepinephrine (NE) in regulating the activity of putative nociceptive modulatory neurons in the rostral ventromedial medulla (RVM), assessed the effects of alpha-adrenergic receptor-selective agents on the nociceptive threshold (as measured by the tail-flick withdrawal response on noxious heat). These microinjection studies were carried out in the barbiturate-anesthetized rat, a preparation which is favourable for acute neurophysiological studies. The data obtained demonstrate that, as observed by others in the awake animal, activation of alpha 2-adrenergic receptors in the RVM produces hypoalgesia. However, unlike in the awake animal, when antagonists selective for either the alpha 1- or alpha 2-adrenergic receptor are microinjected alone into the RVM there is no change in the nociceptive threshold. These data suggest that the alpha 2-adrenergic receptor has a postsynaptic location and that barbiturate anaesthesia suppresses a tonically active or noxious stimulus-activated noradrenergic input to the RVM that is present in the awake animal.     

Source of Stress-Induced Increase in Plasma Met-Enkephalin in Rats: Contribution of Adrenal Medulla and/or Sympathetic Nerves*

The contribution of the adrenal medulla and/or the sympathetic nerves to the plasma levels of Met-enkephalin was investigated. Rats were divided into four groups: sham-operated/saline, sham-operated/guanethidine, adrenal-demedullated/saline, demedulla-ted/guanethidine. After 4 weeks of injection with either saline or guanethidine (25 mg/kg/day), animals were cannulated in the left carotid artery for blood sampling. Three days later, blood samples were taken before and at 2 and 30 min of restraint stress. Adrenal demedullation lowered basal plasma epinephrine levels markedly and prevented entirely the increase induced by restraint stress. Chronic guanethidine treatment lowered basal plasma norepinephrine levels and decreased the response to stress. Guanethidine treatment increased the basal plasma epinephrine level without affecting the response to stress. The combination of guanethidine plus adrenal demedullation lowered basal plasma concentrations of all three catecholamines and further attenuated the norepinephrine response. Restraint stress increased plasma native and peptidase-derivable Met-enkephalin. Adrenal demedullation, resulting in greater than 95% depletion of adrenal catecholamines and significant depletion of adrenal Met-enkephalin, did not inhibit the stress-induced increase in plasma Met-enkephalin, and in fact, was associated with a potentiated response to stress. Guanethidine treatment with or without demedullation increased baseline plasma native Met-enkephalin and abolished the stress-induced increase in plasma native and peptidase-derivable Met-enkephalin. Thus, the stress-induced increase in plasma Metenkephalin results from release from sympathetic nerves, rather than adrenal medulla. However, the sympathetic nerves and adrenal medulla together do not appear to account entirely for basal concentrations of circulating Met-enkephalin. Hepatic portal vein plasma concentration of native Met-enkephalin was greater than that in the carotid artery, suggesting contribution from the gastrointestinal tract; however, evisceration did not decrease plasma native Met-enkephalin. Some compensatory mechanism results in elevation of basal plasma native Met-enkephalin in sympathectomized rats. Also, in the absence of the adrenal medulla there is a compensatory increase in the amount of Met-enkephalin released into the circulation in response to stress.     

Plasma epinephrine modulates the cerebrovasodilation evoked by electrical stimulation of dorsal medulla

We examined whether plasma epinephrine contributes to the increase in regional cerebral blood flow (rCBF) evoked by electrical stimulation of the dorsal medullary reticular formation (DMRF). Rats were anesthetized (alpha-chloralose, 30 mg/kg, s.c.), paralyzed and artificially ventilated. The DMRF was electrically stimulated through microelectrodes stereotaxically implanted. During stimulation, blood gases and arterial pressure were monitored and maintained within normal range. rCBF was determined in 11 dissected brain regions using the [14C]iodoantipyrine technique. Plasma epinephrine and norepinephrine were measured radioenzymatically in rats with intact adrenals or adrenalectomy, and with or without infusion of epinephrine. DMRF stimulation induced widespread increases in rCBF associated with a 50-fold increase in plasma epinephrine and a 20-fold increase in norepinephrine without changes in the electroencephalogram. In contrast, stimulation of the adjacent medial longitudinal fasciculus had no effect upon rCBF or plasma catecholamines. Acute bilateral adrenalectomy produced regionally selective reductions in the stimulation-coupled increases in rCBF throughout brain (P less than 0.05). Infusion of epinephrine in adrenalectomized rats to levels comparable to those observed in intact animals during DMRF stimulation did not by itself modify rCBF. However, when infused in conjunction with stimulation of the DMRF, but not medial longitudinal fasciculus, epinephrine fully restored the stimulus-related increases in rCBF in all brain regions to levels comparable to those observed in intact rats. We conclude that stimulation of the DMRF elevates rCBF through two mechanisms; by a neurally-mediated increase in local metabolism and thereby flow (adrenal independent secondary vasodilation) and by releasing epinephrine from adrenal medulla which secondarily acts to increase rCBF by an action on brain.     

Development of cardiac sympathetic and adrenal-medullary responses in borderline hypertensive rats

Borderline hypertensive (BHR) rats are the first generation offspring of a cross of spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) normotensive rats. In adulthood, BHRs have systolic blood pressures in the 140-160 mm Hg range. If subjected to chronic stress paradigms, however, BHRs develop sustained and permanent elevations in systolic blood pressure (180-200 mm Hg). In the present study, we examined the functional development of cardiac and adrenal medullary responses to reflex activation of the sympathetic nervous system in preweanling BHR and WKY rats. Pups of the two groups were injected with insulin or saline at 4, 8, 12, or 16 days of age and sacrificed 3 h later. Insulin produces an acute lowering of blood glucose which is attended by a centrally mediated increase in sympathetic activity. The induction of ornithine decarboxylase (ODC) activity in heart and the depletion of epinephrine from the adrenal medulla were biochemical indicators of functional sympathetic neurotransmission. WKY and BHR pups had similar levels of cardiac ODC activity under basal conditions and following administration of insulin. In contrast, BHRs had higher amounts of adrenal norepinephrine and epinephrine from 4 to 16 days of age and greater depletion of adrenal epinephrine following insulin administration at 8, 12 and 16 days of age. These findings indicate that BHRs have a greater capacity for catecholamine biosynthesis, storage and release in the adrenal medulla during the preweanling period compared to age-matched normotensive WKY controls. This alteration in the adrenal medulla during the preweanling period may contribute to the susceptibility of adult BHR rats to stress-induced hypertension.     

β-Endorphin-induced increases in plasma epinephrine, norepinephrine and dopamine in rats: inhibition of adrenomedullary response by intracerebral somatostatin

Synthetic human β-endorphin, 7.25 nmol intracisternally, in unanesthetized, freely moving, chronically cannulated, adult male rats increased plasma concentrations of all 3 catecholamines: epinephrine, norepinephrine and dopamine, for the 2 h period studied. Blockade of these endorphin effects by the prior systemic administration of naloxone supports mediation of the effects at opioid receptors. Acute systemic administration of guanethidine, which decreases norepinephrine release induced by sympathetic nerve stimulation, blunted the plasma norepinephrine response to intracerebral β-endorphin. Thus, it seems likely that in addition to secretion by adrenal medulla a considerable portion of the β-endorphin-induced increase in norepinephrine is derived from sympathetic nerve endings. Simultaneous intracisternal administration of another neuropeptide, somatostatin, together with β-endorphin markedly inhibited the plasma epinephrine response to β-endorphin, while decreasing the dopamine and norepinephrine responses to a much lesser degree. The data suggest that β-endorphin stimulates central sympathetic outflow to both adrenal medulla and sympathetic nerve endings, and further that somatostatin inhibits the effect of endorphin to stimulate outflow to adrenal medulla but does not affect outflow to sympathetic nerve endings.     

Evidence for involvement of an adrenal catecholamine in the beta-adrenergic inhibition of oxytocin release in lactating rats

Adrenergic systems exert dual control over the release of oxytocin (OT) in rats, with stimulation of alpha-adrenergic receptors exciting, and stimulation of beta-adrenergic receptors inhibiting, release of this neurohormone. Because suckling stimulation also releases epinephrine from the adrenal medulla, the present experiments tested whether catecholamines of adrenal origin may participate in the adrenergic regulation of OT release during lactation. In two independent experiments, adrenal demedullation of rats in midlactation did not alter the basal plasma levels of OT, but markedly enhanced the suckling-induced release of OT, suggesting an inhibitory action of an adrenal catecholamine. The OT release induced by suckling in both sham-operated and adrenal demedullated rats was prevented by stimulation of beta-adrenergic receptors with isoproterenol. Conversely, blockade of beta-adrenergic receptors with propranolol prevented the inhibitory effects of isoproterenol, and when given alone, mimicked the effects of demedullation to enhance suckling-induced OT release. Stimulation of peripheral alpha-adrenergic receptors with phenylephrine did not affect either basal or suckling-induced OT release, but blockade of alpha-adrenergic receptors with phentolamine also completely prevented the release of OT by suckling. These data support the concept that stimulation of beta-adrenergic receptors inhibits OT secretion, and further suggest that this may be due, at least in part, to an action of an adrenal catecholamine, which may act centrally and/or directly on the neurohypophysis. The present results also provide further evidence that activation of central, but not peripheral, alpha-adrenergic mechanisms is necessary for suckling-induced OT release.     

Sexual dimorphism in endothelin-1 induced mechanical hyperalgesia in the rat

While the onset of mechanical hyperalgesia induced by endothelin-1 was delayed in female rats, compared to males, the duration was much longer. Given that the repeated test stimulus used to assess nociceptive threshold enhances hyperalgesia, a phenomenon we have referred to as stimulus-induced enhancement of hyperalgesia, we also evaluated for sexual dimorphism in the impact of repeated application of the mechanical test stimulus on endothelin-1 hyperalgesia. In male and female rats, endothelin-1 induced hyperalgesia is already maximal at 30 min. At this time stimulus-induced enhancement of hyperalgesia, which is observed only in male rats, persisted for 3-4h. In contrast, in females, it develops only after a very long (15 day) delay, and is still present, without attenuation, at 45 days. Ovariectomy eliminated these differences between male and female rats. These findings suggest marked, ovarian-dependent sexual dimorphism in endothelin-1 induced mechanical hyperalgesia and its enhancement by repeated mechanical stimulation.     

Inhibition of cholinesterase elicits muscarinic receptor-mediated synaptic transmission in the rat adrenal medulla

To determine the role of acetylcholinesterase in cholinergic synaptic transmission in the adrenal medulla in vivo, we applied a dialysis technique to the adrenal medulla of anesthetized rats and examined the effect of acetylcholinesterase inhibitor on the contribution of nicotinic and muscarinic receptors to catecholamine release. Exogenous acetylcholine-induced epinephrine release was inhibited by atropine (a muscarinic receptor antagonist) as well as hexamethonium (a nicotinic receptor antagonist). Endogenous acetylcholine (nerve stimulation)-induced epinephrine release was inhibited by hexamethonium but not atropine. In the presence of neostigmine (an acetylcholinesterase inhibitor), both exogenous and endogenous acetylcholine-induced catecholamine release was enhanced. In either case, epinephrine release was inhibited by atropine as well as hexamethonium. In the presence of eserine (another acetylcholinesterase inhibitor), endogenous acetylcholine-induced epinephrine release was also inhibited by atropine. Exogenous or endogenous acetylcholine-induced norepinephrine release was primarily inhibited by hexamethonium regardless of whether neostigmine was absent or present. In the rat adrenal medulla, the inhibition of acetylcholinesterase not only enhanced cholinergic synaptic transmission but also elicited muscarinic receptor-mediated synaptic transmission for epinephrine release.     

Adrenal epinephrine secretion is not regulated by sympathoinhibitory neurons in the caudal ventrolateral medulla.

By providing the principal inhibitory regulation of the discharge of sympathetic premotor neurons in the rostral ventrolateral medulla (RVLM), neurons in the caudal ventrolateral medulla (CVLM) play a major role in regulating the level of sympathetic nerve activity (SNA) to cardiovascular targets. To determine whether adrenal medullary secretion of epinephrine (EPI) is also regulated by sympathoinhibitory inputs from the CVLM to the RVLM, we compared levels of plasma EPI obtained after disinhibition of RVLM neurons with levels obtained after inhibition of CVLM neurons, both of which result in sustained elevations in arterial blood pressure (AP), SNA, and heart rate (HR). Plasma norepinephrine (NE) concentrations were significantly elevated following bilateral microinjection either of bicuculline (BIC) into the RVLM or of muscimol into the CVLM of urethane/chloralose-anesthetized, artificially-ventilated rats. In sharp contrast, although plasma EPI concentrations were significantly elevated following disinhibition of neurons in the RVLM, they were unchanged by inhibition of neurons in the CVLM. These results demonstrate that the discharge of sympathetic premotor neurons in the RVLM regulating adrenal secretion of EPI is modulated by a tonic, GABA-ergic inhibition that arises from a source that is different from the sympathoinhibitory neurons in the CVLM that project to RVLM sympathetic premotor neurons controlling vasoconstrictor and cardiac targets.     

Effects of a specific beta 2-receptor blocker in neuroleptic-induced akathisia

To assess the role of blockade of beta-receptor subpopulations in the treatment of neuroleptic-induced akathisia (NIA), the specific beta 2-antagonist ICI 118,551 was compared to placebo in a double-blind study. After a baseline evaluation on placebo, patients were treated with ICI 118,551 or placebo. Five of six patients treated with ICI 118,551 showed improvements in NIA, while only one of four patients improved on placebo. Patients were then treated openly with propranolol, a mixed beta 1, beta 2-antagonist. Compared to ICI 118,551, no further improvement on objective measures of akathisia was seen on propranolol. Mean subjective assessments of NIA declined on propranolol, but changes were variable and not statistically significant.