Neural Sites Of Action Research Articles

Nonneural Androgen Receptors Affect Sexual Differentiation of Brain and Behavior.

Testosterone, acting via estrogenic and androgenic pathways, is the major endocrine mechanism promoting sexual differentiation of the mammalian nervous system and behavior, but we have an incomplete knowledge of which cells and tissues mediate these effects. To distinguish between neural and nonneural actions of androgens in sexual differentiation of brain and behavior, we generated a loxP-based transgenic mouse, which overexpresses androgen receptors (ARs) when activated by Cre. We used this transgene to overexpress AR globally in all tissues using a cytomegalovirus (CMV)-Cre driver (CMV-AR), and we used a Nestin-Cre driver to overexpress AR only in neural tissue (Nes-AR). We then examined whether neural or global AR overexpression can affect socio-sexual behaviors using a resident-intruder paradigm. We found that both neural and global AR overexpression resulted in decreased aggressive behaviors and increased thrusting during mounting of intruders, consistent with a neural site of action. Global, but not neural, AR overexpression in males led to an increase in same-sex anogenital investigation. Together, these results suggest novel roles for nonneural AR in sexual differentiation of mice, and indicate that excess AR can lead to a paradoxical reduction of male-typical behavior.

Central Nervous System Acting Drugs in Treatment of Migraine Headache

Migraine is a primary headache disorder with an unknown pathophysiology. The growing evidence in recent years indicates migraine being a brain disorder, a sensory dysmodulation, and a system failure of normal sensory processing of the brainstem that involves the vascular tone and pain. At the moment, triptan family and NSAIDs are the first choice drugs for the treatment of acute migraine. There are several prophylactic drugs including the antiepileptic drugs (AEDs), betablockers, and Ca2+ channel blockers that are used for the treatment of migraine. Although many drugs including the triptans, NSAIDs, and others target the peripheral sites of activation, several novel drugs are being developed to target neural sites of action in the central nervous system (CNS). The first trigeminal synapses in the brain stem as well as the ascending and descending pathways and higher brain centers are involved in the transmission of pain and therefore be the main targets of several drugs some of which are in clinical trials. Central sensitization may also aggravate the headache and some drugs tend to alleviate pain by targeting neurotransmitters, receptors, or signalling molecules involved in this phenomenon. This article discusses the CNS acting novel drugs and those that are currently in use for the treatment of migraine.

Acute Migraine Therapy: New Drugs and New Approaches

Opinion StatementThe conceptual shift of our understanding of migraine from a vascular disorder to a brain disorder has dramatically altered the approach to the development of new medicines in the field. Current pharmacologic treatments of acute migraine consist of nonspecific and relatively specific agents. Migraine-specific drugs comprise two classes, the ergot alkaloid derivatives and the triptans, serotonin 5-HT1B/1D receptor agonists. The ergots, consisting of ergotamine and dihydroergotamine (DHE), are the oldest specific antimigraine drugs available and are considered relatively safe and effective. Ergotamine has been used less extensively because of its adverse effects; DHE is better tolerated. The triptan era, beginning in the 1990s, was a period of considerable change, although these medicines retained vasoconstrictor actions. New methods of delivering older drugs include orally inhaled DHE and the transdermal formulation of sumatriptan, both currently under study. Novel medicines being developed are targeted at neural sites of action. Serotonin 5-HT1F receptor agonists have proven effective in phase II studies and have no vascular actions. Calcitonin gene-related peptide (CGRP) receptor antagonists are another promising nonvasoconstrictor approach to treating acute migraine. Olcegepant (BIBN4096BS) and telcagepant (MK-0974) have been shown to be safe and effective in phase I, II, and (for telcagepant) phase III clinical trials. Other targets under investigation include glutamate (AMPA/kainate), TRPV1, prostanoid EP4, and nitric oxide synthase. With new neural targets and the potential for therapeutic advances, the next era of antimigraine medications is near.

Effects of neuropeptide Y and substance P on antigen-induced ion secretion in rat jejunum.

We previously described a model of intestinal hypersensitivity in which isolated gut segments from sensitized rats demonstrated a rapid epithelial secretory response to luminal antigen that was mediated by mucosal mast cells and capsaicin-sensitive nerves. In this study, we examined the ability of the inhibitory neuropeptide, neuropeptide Y (NPY), to diminish the antigen-induced secretory response. Rats were sensitized to egg albumin (EA), and 12-14 days later, jejunal tissue was excised and mounted in Ussing chambers. NPY inhibited the short-circuit current (Isc) increase and Cl- secretion evoked by addition of EA to the luminal side of the tissue; neural blockade with tetrodotoxin (TTX) had a similar inhibitory effect. In contrast, NPY was much less effective, and TTX was completely ineffective, on the response to serosal antigen. Additional experiments examined the cell target for NPY action. NPY and TTX almost abolished the Isc response to electrical transmural stimulation of enteric nerves, suggesting a possible neural site of action. In addition, NPY significantly reduced baseline Isc; this inhibition involved both TTX-dependent and TTX-independent components. Because nerves were previously shown to facilitate antigen uptake and substance P was implicated in the response to only luminal antigen, we postulated that NPY was inhibiting nerves that facilitate antigen transport from the lumen to effector cells in the lamina propria. We therefore examined the effect of exogenous substance P added after NPY inhibition. Substance P restored the luminal antigen-induced secretory response to pretreatment values. We conclude that the neuropeptides play a significant role in immunophysiology by acting at neural and epithelial sites in the intestinal mucosa.

Effects of opioid antagonists naloxone and naltrexone on neuropeptide Y-induced feeding and brown fat thermogenesis in the rat. Neural site of action.

Neuropeptide Y administered intracerebroventricularly and into the paraventricular nucleus of the hypothalamus stimulates feeding and decreases brown adipose tissue thermogenesis. Although specific neuropeptide Y antagonists are not yet available, previous studies had shown that the opioid antagonist naloxone blocked neuropeptide Y-induced feeding when both drugs were injected intracerebroventricularly. We wanted to find out if naloxone injected into specific brain sites would block neuropeptide Y effects on feeding and brown fat thermogenesis. Rats were double injected in specific brain sites with neuropeptide Y and either naloxone or naltrexone (a congener of naloxone). Food intake and brown fat measures were assessed. Naloxone or naltrexone in the paraventricular nucleus weakly decreased paraventricular nucleus neuropeptide Y-induced feeding and did not affect neuropeptide Y-induced reductions in brown fat activity. Peripheral naloxone blocked intracerebroventricular neuropeptide Y-induced feeding and brown fat alterations. Fourth ventricular naloxone decreased paraventricular nucleus neuropeptide Y-induced feeding, and naltrexone given into the nucleus of the solitary tract blocked paraventricular nucleus neuropeptide Y-induced alterations in feeding and brown fat. These data indicate that neuropeptide Y in the paraventricular nucleus may act on feeding and brown fat thermogenesis through opioidergic pathways in the nucleus of the solitary tract.

Morphine-induced inhibition of ovulation in normally cycling rats: Neural site of action

Intracerebral injection of morphine ( 3 μg 0.2 μl of solvent) on the day of proestrus at 1200 hr bilaterally in the medial preoptic area (mPOA) and median eminence-arcuate (ME-ARC) region inhibited ovulation in the cycling female rats. The morphine antagonist, lethidrone ( 2 μg 0.2 μl of solvent) when injected in the mPOA and ME-ARC region followed by intraperitoneal morphine ( 3 mg 100 g body weight) administration, was found to reverse the ovulation blocking action of this opiate. Implantation sites at which morphine was effective in blocking ovulation were restricted to a narrow medial band encompassing the mPOA and ME-ARC region. Our data are consistent with the view that the endogenous opioid peptides in mPOA and ME-ARC region of the hypothalamus may be involved in the physiological regulation of the central neural events which lead to ovulation in the rat.

In vitro luteinizing hormone-releasing hormone release from superfused rat hypothalami: site of action of progesterone and effect of estrogen priming.

The study examined the effect of estrogen priming on progesterone (P4)-induced LHRH release, the tissue site of action of P4, and the effect of 5 alpha-dihydroxyprogesterone (5 alpha-DHP) on LHRH release from hypothalamic fragments superfused in vitro. Immature female rats were ovariectomized (OVX) and, at 28 days of age, Silastic capsules containing estradiol (E2) were implanted. Two days later, animals were killed and hypothalamic fragments were removed and transferred to superfusion chambers. The hypothalamic units received P4 or 5 alpha-DHP delivered in an intermittent mode (10-min on, 20-min off). LHRH was determined in perfusates by RIA. After the input characteristics of different infusion modes (single pulses, intermittent, and continuous) of P4 infused into superfusion chambers were assessed, an intermittent infusion mode (10-min on, 20-min off) was selected for further examinations. In the mediobasal hypothalamic-anterior hypothalamic-preoptic area (MBH-AHA-POA) tissue preparations, we observed: 1) an infusion of 5 alpha-DHP was ineffective in stimulating LHRH release; 2) the release pattern of LHRH in response to three different P4 doses (10, 20, and 50 ng/ml) was similar in terms of percent changes (202% to 219% over control values); and 3) E2 priming was absolutely required for P4-stimulated LHRH release, and this requirement appeared to be dose dependent. Upon an examination of three hypothalamic tissue boundaries [the MBH, the POA-suprachiasmatic nuclei (POA-SCN), and the median eminence (ME)] to better delineate the in vitro site of action of P4 on LHRH release, it was demonstrated that the MBH responded upon P4 infusion, whereas the POA-SCN was unable to do so. The ME also responded upon P4 infusion, and LHRH release followed closely the pulsatile administration of P4 since upon each challenge of the steroid at the concentration of 10 or 20 ng/ml, a significant rise in LHRH release occurred. However, the temporal patterns of LHRH release from the ME appears to be different from those obtained from the MBH as well as the MBH-AHA-POA. These observations demonstrate that an intermittent infusion of P4, but not 5 alpha-DHP, is effective in activating the neural LHRH apparatus. Estrogen is an obligatory requirement for this P4-stimulated LHRH release, and the neural site of action of P4 resides within the MBH. However, this steroid also can act directly upon the ME nerve terminals to release LHRH.

Dopaminergic and serotonergic involvement in opiate-induced prolactin release in monkeys.

The present experiments were performed to determine the site of action (hypothalamic or hypophyseal) and the mechanism (dopaminergic or serotonergic) by which morphine increases PRL in monkeys (Macaca mulatta and Macaca nemestrina). To determine the site of action, 9 mg morphine were injected iv to four intact and four pituitary stalk-sectioned monkeys. PRL concentrations rose significantly (P less than 0.01) from less than 5 ng/ml to an average maximum value of 208 +/- 20 ng/ml at 15 min in intact animals, but remained unchanged in pituitary stalk-sectioned animals. There was a significant reduction (P less than 0.01) of this response in intact monkeys that received 5 mg L-dopa, iv, 5 min before the morphine stimulus. In these animals, PRL only rose to 100 +/- 46 ng/ml. In contrast, the PRL response in four monkeys pretreated with 5 or 20 mg methysergide, iv (a serotonin receptor blocker), 5 min before the opiate stimulus was not different from in controls. Likewise, the daily administration of 100 mg p-chlorophenylalanine, sc (a serotonin synthesis blocker), for 6 days failed to alter the PRL response to morphine. These data suggest that opiates increase PRL via a neural site of action and that the mechanism may involve dopaminergic but not serotonergic pathways.