Dose-different effects of orexin-A on the renal sympathetic nerve and blood pressure in urethane-anesthetized rats

Previous studies have demonstrated that central injection of orexin-A affects renal sympathetic nerve activity (RSNA) and blood pressure (BP) in both anesthetized and unanesthetized rats. In the present study, we examined, using urethane-anesthetized rats, the dose-dependent effects of intravenous (iv) or intralateral cerebral ventricular (LCV) injection of various doses of orexin-A on RSNA and BP. We found that injection of a low dose of orexin-A (10 ng iv or 0.01 ng LCV) suppressed RSNA and BP significantly. Conversely, a high dose (1000 ng iv or 10 ng LCV) of orexin-A elevated both RSNA and BP significantly. Pretreatment with either iv or LCV injection of thioperamide, a histaminergic H(3)-receptor antagonist, eliminated the effects of a low dose of orexin-A on both RSNA and BP. Both iv and LCV injection of diphenhydramine, a histaminergic H(1)-receptor antagonist, abolished the effects of a high dose of orexin-A on RSNA and BP. Furthermore, bilateral lesions of the hypothalamic suprachiasmatic nucleus (SCN) abolished the effects of both low and high doses of orexin-A on RSNA and BP. These findings suggest that orexin-A affects RSNA and BP in a dose-dependent manner and that the SCN and histaminergic nerve may be involved in the dose-different effects of orexin-A in rats.     

Effects of central injection of L-carnosine on sympathetic nerve activity innervating brown adipose tissue and body temperature in rats

In the present study, using urethane-anesthetized rats, we examined the effects of intralateral cerebral ventricular (LCV) injection of various doses of L-carnosine on neural activity innervating brown adipose tissue (BAT-SNA) and body temperature (BT). We found that injection of a low dose of L-carnosine (0.01 microg) suppressed BAT-SNA significantly. Conversely, a high dose (100 microg) of L-carnosine significantly elevated BAT-SNA. In the light period (14:00), brown adipose tissue temperature (BAT-T) and BT were suppressed after low and elevated after high dose injection of L-carnosine whereas in the dark period (2:00), these parameters remained unchanged with L-carnosine treatment. Bilateral lesions of the hypothalamic suprachiasmatic nucleus (SCN) abolished the effects of low and high doses of L-carnosine on BAT-SNA, BAT-T and BT. Furthermore, high dose treatment with L-carnosine altered c-Fos induction in the SCN and the PVN. These results suggest that l-carnosine affects BAT-SNA, BAT-T and BT in a dose-dependent manner in the rat, and that the SCN may be involved in these effects.     

Chronic blockade of brain "ouabain" prevents sympathetic hyper-reactivity and impairment of acute baroreflex resetting in rats with congestive heart failure

In rats with congestive heart failure (CHF) post myocardial infarction (MI) acute blockade of brain "ouabain" reverses sympathetic hyperactivity and chronic blockade prevents the desensitization of baroreflex function. This study was conducted to determine: i) if chronic blockade of brain "ouabain" maintains normal sympathetic reactivity; and ii) if acute baroreflex resetting (another parameter of baroreflex function) also becomes impaired, and if so, does brain "ouabain" contribute to impairment in acute baroreflex resetting. CHF post MI was induced by acute coronary artery ligation in Wistar rats. Animals were treated with 200 microg x day(-1) i.c.v. or i.v. Fab fragments (which bind brain "ouabain" with high affinity), or treated with 200 microg x day(-1) i.c.v. gamma-globulins (control group). The length of treatment was 0.5-8 weeks or 4-8 weeks post MI. At 8 weeks mean arterial pressure (MAP), central venous pressure (CVP), heart rate (HR), and renal sympathetic nerve activity (RSNA) were recorded in concious rats at rest and in response to: i) air-jet stress, ii) i.c.v. guanabenz (an alpha2-adrenoceptor agonist), and iii) a 30 min i.v. infusion of nitroprusside (NP). Excitatory responses to air stress and inhibitory responses to guanabenz of MAP, HR, and RSNA were significantly enhanced in rats with CHF versus the sham-operated treated group. This enhancement was prevented in the CHF group treated with i.c.v., but not i.v., Fab. Nitroprusside induced a sustained decrease in MAP (approximately 25 mmHg) and a transient decrease in CVP. Heart rate and RSNA increased significantly within 1 min of beginning the infusion. The peak increases as well as the product of changes in MAP-HR and RSNA-HR were significantly smaller in rats with CHF treated with gamma-globulins versus sham rats and versus CHF rats treated with i.c.v. Fab. In sham-operated rats and CHF rats treated with i.c.v. Fab, RSNA and HR began to decrease within 3-4 min of beginning the NP infusion and had returned to baseline by 20 min. In contrast, RSNA and HR remained increased throughout the infusion in the CHF rats treated with gamma-globulins. These data indicate that in rats with CHF acute resetting of the arterial baroreflex in response to a lower BP becomes impaired, and chronic blockade of brain "ouabain" prevents both this change in baroreflex resetting as well as sympathetic hyperactivity.     

Intravenous urocortin II decreases blood pressure through CRF(2) receptor in rats

Urocortin II (Ucn II) is a new member of the corticotropin-releasing factor (CRF) family that binds selectively to the CRF subtype 2 receptor (CRF(2)). CRF or urocortin injected intravenously (i.v.) induced hypotension. We investigated the influence of iv human Ucn II (hUcn II) on basal mean blood pressure (MAP) and on the sympathetic mediated hypertensive response to TRH analog, RX-77368 injected intracisternally (i.c.) 20 min after hUcn II in urethane-anesthetized rats. Ucn II (3, 10, and 30 microg/kg, i.v.) significantly decreased basal MAP from baseline by -20.9+/-6.5, -21.3+/-5.4 and -46.8+/-6.5 mm Hg, respectively, after 10 min. RX-77368 (30 ng, i.c.) elevated MAP for over 90 min with a maximal hypertensive response at 20 min. Ucn II (3, 10, and 30 microg/kg, i.v.) did not alter the 20 min net rise in MAP induced by RX-77368 (35.7+/-7.1, 32.6+/-3.3 and 24.6+/-6.9 mm Hg, respectively) compared with vehicle (33.6+/-4.3 mm Hg). The selective CRF(2) antagonist, astressin(2)-B (60 microg/kg, i.v.) abolished hUcn II hypotensive action while having no effect on basal MAP. These data show that iv hUcn II induces hypotension through peripheral CRF(2) receptor while not altering the responsiveness to sympathetic nervous system-mediated rise in MAP.     

Possible role of L-carnosine in the regulation of blood glucose through controlling autonomic nerves

Mammalian muscles synthesize L-carnosine, but its roles were unknown. Previously, we found in rats that the administration of a certain amount of L-carnosine elicited an inhibition of the hyperglycemia induced by the injection of 2-deoxy-D-glucose (2DG) into the lateral cerebral ventricle (LCV), and that intravenous injection of L-carnosine inhibited sympathetic nerves and facilitated the parasympathetic nerve. Moreover, the suppressive effect of L-carnosine on the hyperglycemia induced by 2DG was eliminated by thioperamide, a histaminergic H3 receptor. These findings suggested that L-carnosine might control the blood glucose level through regulating autonomic nerves via H3 receptor. To further clarify the function of L-carnosine, we examined its role in the control of the blood glucose. In this experiment, the following results were observed in rats: (i) A certain amount (0.01% or 0.001%) but not a larger amount (0.1%) of L-carnosine given as a diet suppressed the hyperglycemia induced by LCV-injection of 2DG (2DG-hyperglycemia); (ii) LCV-injection but not the injection into the intraperitoneal space (IP) of a certain amount of L-histidine suppressed the 2DG-hyperglycemia; (iii) treatments of diphenhydramine, an H1 antagonist, and alpha-fluoromethylhistidine, an inhibitor of histamine-synthesizing enzyme, reduced the 2DG-hyperglycemia; (iv) the plasma L-carnosine concentration and carnosinase activity showed daily changes; (v) the plasma L-carnosine concentration was significantly lower in the streptozotocin-diabetic rats; (vi) exercise by a running wheel tended to increase carnosine synthase activity in the gastrocnemius muscle and elevated the plasma L-carnosine concentration in the dark (active) period, and enhanced the plasma carnosinase activity in the light period; (vii) IP-injection of certain amount of L-carnosine stimulated the feeding response to IP-injection of 2DG. These findings suggest a possibility that L-carnosine released from muscles due to exercise functions to reduce the blood glucose level through the regulation of the autonomic nerves.     

Stimulatory effects of endogenous and exogenous nitric oxide on gastric acid secretion in anesthetized rats

We previously reported the stimulatory effect of endogenous nitric oxide (NO) on gastric acid secretion in the isolated mouse whole stomach and histamine release from gastric histamine-containing cells. In the present study, we investigated the effects of endogenous and exogenous NO on gastric acid secretion in urethane-anesthetized rats. Acid secretion was studied in gastric-cannulated rats stimulated with several secretagogues under urethane anesthesia. The acid secretory response to the muscarinic receptor agonist bethanechol (2 mg/kg, s.c.), the cholecystokinin(2) receptor agonist pentagastrin (20 microg/kg, s.c.) or the centrally acting secretagogue 2-deoxy-D-glucose (200 mg/kg, i.v.) was dose-dependently inhibited by the NO synthase inhibitor N(omega)-nitro-L-arginine (L-NNA, 10 or 50 mg/kg, i.v.). This inhibitory effect of L-NNA was reversed by a substrate of NO synthase, L-arginine (200 mg/kg, i.v.), but not by D-arginine. The histamine H(2) receptor antagonist famotidine (1 mg/kg, i.v.) completely inhibited the acid secretory response to bethanechol, pentagastrin or 2-deoxy-D-glucose, showing that all of these secretagogues induced gastric acid secretion mainly through histamine release from gastric enterochromaffin-like cells (ECL cells). On the other hand, histamine (10 mg/kg, s.c.)-induced gastric acid secretion was not inhibited by pretreatment with L-NNA. The NO donor sodium nitroprusside (0.3-3 mg/kg, i.v.) also dose-dependently induced an increase in acid secretion. The sodium nitroprusside-induced gastric acid secretion was significantly inhibited by famotidine or by the soluble guanylate cyclase inhibitor methylene blue (50 mg/kg, i.v.). These results suggest that NO is involved in the gastric acid secretion mediated by histamine release from gastric ECL cells.     

Influence of cyclooxygenase inhibitors on the central histaminergic stimulations of hypothalamic - pituitary - adrenal axis.

Brain histamine participates in central regulation of the hypothalamic-pituitary-adrenal (HPA) axis. Endogenous prostaglandins modulate signal transduction of different neurotransmitters involved in activation of HPA axis. In the present experiment we investigated whether endogenous prostaglandins are involved in the stimulation of ACTH and corticosterone secretion by histaminergic systems in the rat brain. Histamine (50 microg), histamine-trifluoromethyl-toluidine derivative (HTMT, 75microg) a selective and potent H(1)-receptor agonist, and amthamine (50 microg) a H(2)-receptor agonist given intracerebroventricularly (i.c.v.) to non-anesthetized rats considerably increased ACTH and corticosterone secretion 1h after administration. A non-selective cyclooxygenase inhibitor indomethacin (2 mg/kg i.p. or 10 microg i.c.v.), piroxicam (0.02 and 0.2 microg i.c.v.) a more potent antagonist of constitutive cyclooxygenase (COX-1) and compound NS-398 (0.1 and 1.0 microg i.c.v.), a selective inhibitor of inducible cyclooxygenase (COX-2) were given 15 min before histamine and histamine receptor agonists. One hour after the last injection trunk blood from decapitated rats was collected for hormones determination. The histamine-induced ACTH and corticosterone secretion was significantly diminished by piroxicam and was not markedly altered by indomethacin and compound NS-398. The HTMT-elicited increase in ACTH and corticosterone secretion was significantly prevented by indomethacin and was not affected by piroxicam or compound NS-398. The amthamine-evoked increase in ACTH and corticosterone secretion was not markedly influenced by any cyclooxygenase blocker applied in the present experiment. These results indicate that the histamine H(1)-receptor transmitted central stimulation of the HPA axis is considerably mediated by prostaglandins generated by consititutive cyclooxygenase, whereas stimulation transmitted via H(2)-receptor does not significantly depend on endogenous prostaglandins mediation.     

Peripheral mechanisms involved in the pressor and bradycardic effects of centrally administered arachidonic acid

In the current study, we aimed to determine the cardiovascular effects of arachidonic acid and peripheral mechanisms mediated these effects in normotensive conscious rats. Studies were performed in male Sprague Dawley rats. Arachidonic acid was injected intracerebroventricularly (i.c.v.) at the doses of 75, 150 or 300 microg and it caused dose- and time-dependent increase in mean arterial pressure and decrease in heart rate in normal conditions. Maximal effects were observed 10 min after 150 and 300 microg dose of arachidonic acid and lasted within 30 min. In order to evaluate the role of main peripheral hormonal mechanisms in those cardiovascular effects, plasma adrenaline, noradrenaline, vasopressin levels and renin activity were measured after arachidonic acid (150 microg; i.c.v.) injection. Centrally injected arachidonic acid increased plasma levels of all these hormones and renin activity. Intravenous pretreatments with prazosin (0.5 mg/kg), an alpha1 adrenoceptor antagonist, [beta-mercapto-beta,beta-cyclopentamethylenepropionyl1, O-Me-Tyr2-Arg8]-vasopressin (10 microg/kg), a vasopressin V1 receptor antagonist, or saralasin (250 microg/kg), an angiotensin II receptor antagonist, partially blocked the pressor response to arachidonic acid (150 microg; i.c.v.) while combined administration of these three antagonists completely abolished the effect. Moreover, both individual and combined antagonist pretreatments fully blocked the bradycardic effect of arachidonic acid. In conclusion, our findings show that centrally administered arachidonic acid increases mean arterial pressure and decreases heart rate in normotensive conscious rats and the increases in plasma adrenaline, noradrenaline, vasopressin levels and renin activity appear to mediate the cardiovascular effects of the drug.     

Effects of intraventricular administration of vasoactive intestinal peptide and neurotensin on salivary secretion and blood pressure in the rat

Studies were carried out to investigate central actions of vasoactive intestinal polypeptide (VIP) and neurotensin (NT) on systemic blood pressure (BP), heart rate (HR) and salivary secretion in urethane-anesthetized male rats. Intraventricular (i.c.v.) administration of VIP caused dose-related increases in BP, HR and salivary secretion. Nearly maximum values were obtained at the dose of 2.0 micrograms for BP and 10.0 micrograms for salivary secretion, whereas the increase in HR did not attain the maximum even with the dose of 10.0 micrograms. Administration of hexamethonium (i.v.) completely blocked the increasing response of BP and HR, and the administration of pimozide (i.p.) or phenoxybenzamine (i.v.) reduced them. The increasing response of salivary secretion was almost completely blocked by all of the drugs. The administration of NT (i.c.v.) produced no change in the BP, HR and salivary secretion. The present results indicate that, 1) centrally administered VIP may somehow augment the sympathetic nerve discharge and/or adrenal medulla secretion, and 2) central VIP may play a role in the control of salivary regulation, probably through sympathetic nerves.     

激动中枢组胺能受体对应激大鼠颈动脉窦压力感受性反射重调定的影响

应激1周的大鼠,麻醉后弧离双侧颈动脉窦区,将不同窦内压（ISP）与其对应的平均动脉压（MAP）值进行Logistic5个参数曲线拟合。根据所得ISP－MAP关系曲线及其特征参数,分别观察侧脑室(i.c.v.）注射和弧束核（NTS）内注射组胺受体拮抗剂对颈动脉窦压力感受性反射（CSR）的影响,并与相应的非应激CSR水平进行比较。结果如下：（1）应激导致ISP－MAP关系曲线显著全面上移,窦内压和增益（ISP-Gain）关系曲线中部明显下移,反射参数中阈压（TP）、饱和压（SP）、调定点（set point）和最大增益时的窦内压（ISPGmax）值增大,MAP反射变动范围（MAPrange）及反射最大增益（Gmax）减小;（2）I.c.v.H1或H2受体拮抗剂氯苯吡胺（CHL）15μg或西咪替丁（CIM）15μg,在20min内均可明显减弱应激对CSR的上述改变,CIM的这种减弱作用不如CHL的显著;（3）NTS内注射CHL（0.5μg）或CIM（1.5μg）,对应激所致CSR变化的影响与i.c.v.CHL或CIM后的相类似;（4）分别i.c.v.和NTS内注射CHL或CIM后,均不能使应激的CSR水平完全恢复到相应的非应激对照水平。以上结果提示,应激引起CSR重调定,反射敏感性下降;其部分机制可能是激活中枢组胺能系统,通过中枢组胺能受体（H1和H2受体）尤其是H1受体介导而发挥作用;下丘脑－NTS的组胺能通路可能是应激导致CSR重调定的下行通路之一。     

大鼠侧脑室内注射组胺对颈动脉窦压力感受性反射的影响及其中枢机制

在50只麻醉的大鼠孤离双侧颈动脉窦区,将不同窦内压（ISP）与其对应的平均动脉压（MAP）值进行Logistic五参数曲线拟合,根据所得ISP-MAP关系曲线及其特征参数,观察侧脑室注射（i.c.v)组胺（HA）对颈动脉窦压力感受性反射（CSR）的影响,并对其作用机制进行了初步探讨。结果如下：（1）i.c.v.HA(100ng)导致ISP-MAP关系曲线显著上移,ISP和增益（Gain)关系曲线中部明显下移,反射参数中阈压（TP）,饱和压（SP）和最大增益时的窦内压（ISPGmax)值增大,MAP反射变动范围（MAPrange)及反射最大增益（Gmax)减小。（2）预先i.c.v.H1受体拮抗剂氯苯吡胺（CHL,5μg）或H2受体拮抗剂西咪替丁（CIM,15μg）,可明显减弱HA的上述效应,CIM的这种减弱作用不如CHL的显著。（3）预先同时i.c.v.CHL和CIM（分别为5和15μg）,能完全取消HA的效应。（4）预先向孤束核（NTS）内注射CHL（0.5μg）或CIM（1.5μg）,对HA效应的影响与i.c.v.CHL或CIM后的相类似,但NTS内注射CHL或CIM后i.c.v.HA所致的TP变化表现明显下降。以上结果提示,侧脑室给HA使CSR产生快速重调定,反射敏感性下降,功能受抑;其机制是通过中枢HA受体介导,H1受体的作用比H2受体更为明显;下丘脑-NTS的HA能通路可能是HA调节CSR的下行通路之一。NTS处的HA受体在i.c.v.HA抑制CSR的机制中可能发挥重要的作用。     

Peripheral administration of AT1 receptor blockers and pressor responses to central angiotensin II and sodium.

Central administration of AT1 receptor blockers prevents salt-sensitive hypertension and inhibits progression of CHF. We investigated in Wistar rats the effectiveness of peripheral administration of two AT1 receptor blockers, losartan and embusartan, in exerting central AT1 receptor blockade. Losartan or embusartan at doses of 30 and 100 mg/kg were administered subcutaneously (s.c.) as a single dose, or one dose daily for 6 days. The BP responses to intracerebroventricular (i.c.v.) injection of Ang II, i.c.v. infusion of Na+-rich aCSF (0.3 M NaCl), and intravenous (i.v.) injection of Ang II were then measured. Losartan or embusartan at 30 and 100 mg/kg both inhibited the BP increases induced by i.c.v. Ang II and, to a lesser extent, by Na+-rich aCSF. After a single dose, this inhibition was more pronounced for losartan. However, after 6 days of treatment, there were no significant differences between the effects of losartan and embusartan. Losartan and embusartan blocked responses to Ang II i.v. to a similar extent. These results indicate that results from single-dose studies may not reflect the chronic steady-state, and that during chronic treatment both AT1 receptor blockers are similarly effective in inhibiting AT1 receptors in the central nervous system, when assessed by pressor responses to acute increases in CSF Na+ or CSF Ang II.     

Role of brain adrenoceptors in the corticortopin-releasing factor-induced central activation of sympatho-adrenomedullary outflow in rats

We investigated the role played by catecholamine-dependent pathways in modulating the ability of centrally administered corticotropin releasing factor (CRF) to activate sympatho-adrenomedullay outflow, using urethane-anesthetized rats. The CRF (1.5 nmol/animal, i.c.v.)-induced elevations of both plasma noradrenaline and adrenaline were attenuated by phentolamine (a non-selective alpha adrenoceptor antagonist) [125 and 250 microg (0.33 and 0.66 micromol)/animal], Heat (a selective alpha(1) adrenoceptor antagonist) [10 and 30 microg (30 and 90 nmol)/animal, i.c.v.] and clonidine (a selective alpha(2) adrenoceptor agonist) [100 microg (0.375 micromol)/animal, i.c.v.]. On the other hand, the CRF (1.5 nmol/animal, i.c.v.)-induced elevation of both catecholamines was not influenced by RS 79948 (a selective alpha(2) adrenoceptor antagonist) [10 and 30 microg (7.2 and 72 nmol)/animal, i.c.v.]. Furthermore, the CRF (1.5 nmol/animal, i.c.v.)-induced elevation of noradrenaline was attenuated by sotalol (a non-selective beta adrenoceptor antagonist) [125 and 250 microg (0.4 and 0.8 micromol)/animal, i.c.v.], while that of adrenaline was not influenced by sotalol. These results suggest that centrally administered CRF-induced elevation of plasma noradrenaline is mediated by an activation of alpha(1) and beta adrenoceptors in the brain, and that of plasma adrenaline is mediated by an activation of alpha(1) adrenoceptors in the brain. Furthermore, central alpha(2) adrenoceptors are involved in modulating the CRF-induced elevation of both plasma catecholamines.     

Paradoxical effects of intracerebroventricular low-dose opioid antagonists in SHR with chronic pain.

The aim of our study was to investigate the effect of intracerebroventricular (i.c.v.) administration of very low doses of opioid antagonists on the pain threshold, arterial blood pressure and body temperature of spontaneously hypertensive rats (SHR) with chronic pain. We found that low doses of i.c.v. administered naloxone hydrochloride (0.3 microg) or naloxone methiodide (0.4 microg) produce paradoxical hypoalgesia. Similar results were not observed following i.c.v. administration of nor-binaltorphimine (0.6 microg). A paradoxical increase in the severity of hypertension followed i.c.v. opioid antagonist administration. This suggests an involvement of the opioid system in the mechanisms of blood pressure control. The paradoxical results obtained both for pain threshold and blood pressure after low doses of some opioid antagonists seem to confirm the role played by opioid autoreceptors in these effects. Existence of autoreceptors is suggested. Results obtained following i.c.v. administration of nor-binaltorphimine also suggest a role for the kappa autoreceptor (OP2) in the regulatory mechanisms of thermoregulation.     

Cardiovascular responses to intrathecal administration of endomorphins in anesthetized rats

Endomorphins (EMs), the endogenous, potent and selective mu-opioid receptor agonists, have been shown to decrease systemic arterial pressure (SAP) in rats after intravenous (i.v.) administration. In the present study, cardiovascular responses to intrathecal (i.t.) injection of EMs were investigated in urethane-anesthetized rats. It is noteworthy that EMs elicited decreases in SAP and heart rate (HR) in a dose-dependent manner; 10-300nmol/kg were injected intrathecally. Furthermore, these vasodepressor and bradycardic effects were significantly antagonized by naloxone (0.5mg/kg, i.t.). Interestingly, i.t. (5mg/kg) or i.v. (50mg/kg) administrations of N(omega)-nitro-l-arginine methylester (l-NAME) attenuated the vasodepressor and bradycardic effects. Moreover, pretreatment of the rats with muscarinic receptor antagonist atropine (2mg/kg, i.v.) and alpha-adrenoceptor antagonist phentolamine (1mg/kg, i.v.) significantly reduced the vasodepressor effects of EMs. Nevertheless, pretreatment with beta-adrenoceptor antagonist propranolol (2mg/kg, i.v.) could only block the bradycardia effects induced by EMs, but had no significant effects on the hypotension. In summary, all the results suggested that i.t. administration of EMs decreased SAP and HR which were possibly mediated by the activation of opioid receptors in the rat spinal cord. In addition, nitric oxide (NO) release in both the spinal cord and in peripheral tissues might regulate the cardiovascular activities of EMs, and the muscarinic receptor and adrenoceptor played an important role in the regulation of the cardiovascular responses to i.t. administration of EMs.     

The effect of CNS opioid on autonomic nervous and cardiovascular responses in diet-induced obese rats

The intracerebroventricular (i.c.v.) infusion of beta-endorphin can cause either a decrease in blood pressure in normal rats or an increase in obese rats. Diet-induced obesity is associated with an increase of hypothalamic mu opioid receptors. Since beta-endorphins act by opioid receptors, we investigated the effect of CNS mu as well as kappa opioid receptor agonist and antagonist on mean blood pressure (MAP), heart rate (HR) and renal sympathetic nerve activity (RSNA) in male Wistar rats fed either a high fat (HF) (40% fat by weight) or a regular low fat (control) (4% fat by weight) diet. After a 12-week-feeding period the animals were implanted with i.c.v. cannulas and 3-5 days later they were anesthetized and instrumented to record MAP, HR and RSNA. HF rats have higher MAP and the i.c.v. injection of a mu opioid agonist (DAMGO) initially decreased the MAP and then increased MAP, HR and RSNA in the normal animals. The increase was greater in HF animals. The i.c.v. injection of the mu antagonist (beta-FNA) resulted in a significantly greater decrease in MAP in HF animals. beta-FNA increased the RSNA in the HF rats but decreased it in the normal rats. The kappa agonist (dynorphin) decreased MAP in normal rats followed by a return to baseline, but not in HF rats. The kappa antagonist, nor-binaltorphimine (N-BP), increased MAP and RSNA in normal rats and to a lesser extent in HF rats. These findings suggest that rats given a high fat diet have higher blood pressures and a greater mu opioid-mediated responsiveness with a greater mu opioid-mediated autonomic tone. Additionally there is a decreased kappa responsiveness and tone in the HF rats. Both these changes, increased mu and decreased kappa responsiveness could strongly contribute to the increased blood pressure in obese animals.     

The influence of NMDA receptor agonist and antagonist on morphine state-dependent memory of passive avoidance in mice

The measurement of step-down latency in passive avoidance has been used to study memory in laboratory animals. The pre-training injection of 5 mg/kg morphine impaired memory, which was restored when 24 h later the same dose of the drug was administered. To explore the possible involvement of NMDA modulators on morphine-induced memory impairment, we have investigated the effects of intracerebroventricular (i.c.v.) administration of NMDA and the competitive NMDA antagonist, DL-AP5, on morphine-induced memory impairment or recall, on the test day. Morphine (5 mg/kg, s.c.) was administered 30 min before training to induce impairment of memory and 24 h later, 30 min before test to improve it. Pre-test administration of NMDA (0.00001, 0.0001 and 0.001 microg/mouse, i.c.v.) did not alter the retention latency compared to the saline-treated animals. But restored the memory impairment induced by pre-training morphine (5 mg/kg, s.c.). Pre-test administration of DL-AP5 (1, 3.2 and 10 microg/mouse, i.c.v.) by itself decreased the retention latencies. The same doses of DL-AP5 increased pre-training morphine-induced memory impairment. Co-administration of NMDA (0.0001 and 0.001 microg/mouse, i.c.v.) and morphine (5 mg/kg, s.c.) on the test day increased morphine memory improvement. Conversely, DL-AP5 (1, 3.2 and 10 microg/mouse, i.c.v.) inhibited morphine-induced memory recall. It is concluded that NMDA receptors may be involved, at least in part, in morphine state-dependent learning in mice.     

Neurotransmitter-mediated open-field behavioral action of CGRP

The effects of central administration of calcitonin gene-related peptide (CGRP) on open-field activity were examined in male rats. Three doses (250 ng, 500 ng and 1 microg) of CGRP given intracerebroventricularly (i.c.v.) were tested on the ambulatory, rearing and grooming activities of the animals. One microg of peptide significantly decreased the ambulatory activity and increased the rearing and grooming activities 30 min after the treatment. The animals were pretreated with different receptor antagonists in doses which by itself did not affect the behavioural paradigm. The decrease in ambulation induced by CGRP was antagonized by acetylcholine-, opioid-, 5HT-receptor and beta-adrenoceptor antagonists. CGRP induced increase in rearing activity was blocked by naloxone, phenoxybenzamine and propranolol. The CGRP-induced increase in grooming behavior was prevented by atropine, haloperidol, naloxone, methysergide and propranolol. The results suggest that different neurotransmitter systems are involved in the action of CGRP on open-field behavior in rats.     

The effects of delta agonists on locomotor activity in habituated and non-habituated rats

The effects of the delta agonists SNC80 and deltorphin II on ambulation and rearing activity were measured in habituated and non-habituated rats. SNC80 (30, 100, 200, 400 nmol, i.c.v.) and deltorphin II (3, 15, 30, 60 nmol, i.c.v.) induced similar, dose-dependent biphasic locomotor effects in non-habituated subjects. An initial decrease in exploratory activity was associated with anxiogenic signs such as pilo-erection, freezing behaviour and pupil dilation for each drug. Pre-treatment with the delta antagonist naltrindole (10 nmol, i.c.v.) inhibited the depressant effect, but not the subsequent stimulant effect, on locomotor activity in response to 30 nmol deltorphin II in this assay (P<0.05). In habituated rats, deltorphin II (0.03, 0.1, 0.3, 3 nmol, i.c.v.) caused significant, naltrindole-reversible increases in locomotor activity (P<0.05 for all doses) at 1,000-fold lower doses than those required for a similar response to SNC80 (10, 30, 100, 300 nmol, i.c.v.). Pharmacokinetic studies suggest that these compounds penetrate the brain to similar extents following i.c.v. injection. The substantial potency difference between deltorphin II and SNC80 in stimulating locomotor activity in habituated rats suggests pharmacological heterogeneity for these delta opioid receptor agonists.