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Organizationally, the University of Saskatchewan planned to transform from research aligned within five Basic Science Departments in the College of Medicine and in the nondepartmentalized College of Pharmacy and Nutrition to eight interdisciplinary biomedical health clusters from these units. These clusters were aligned and designated by leadership based on common thematic areas of research, anticipating synergies among them. They were balanced as much as possible with respect to research, teaching, and clinical responsibilities—recognizing that it would take time to achieve the desired equilibrium. Two primary goals of this project were the enhancement of Inter-Professional Health Education and Inter-Disciplinary Health Research. This goal had a dual mission; to ensure that the graduate Health Science professionals were better prepared to deliver health care to the province to achieve better patient outcomes by working across disciplines, and second, to build a culture of collaborative Team Science to attract greater levels of research funding that would also ultimately contribute to better patient outcomes.

A 128-channel event-driven ASIC is described which reads out the R3B (Reactions with Relativistic Radioactive Beams) silicon micro vertex tracker. Ionizing particles with energies in the range of 40keV-50MeV are detected, digitized and read out with 12 bit resolution, and time stamped with up to 5ns precision. The ASIC copes with signal charges and detector leakage currents of both polarities and allows charge sharing to be taken into account by reading out the charge from neighboring channels. The ASIC can recover quickly from signals up to 1Gev, can store up to 32 events and can be easily daisy-chained to reduce parallel connections. Outputs can be Manchester encoded to allow for capacitive coupling of the data, and a 128-bit OR of all the channel hits provides a fast trigger output.

The SPEDE spectrometer [1] aims to combine a silicon detector, for the detection of electrons, with the MINIBALL γ-ray detection array for in-beam studies employing radioactive ion beams at the HIE-ISOLDE facility at CERN. The setup will be primarily used for octupole collectivity [2] and shape coexistence studies [3, 4] in Coulomb excitation experiments. In the shape coexistence cases the transitions between states of the same spin and parity have enhanced E0 strength [5]. Additionally the 0→0 transitions, typically present in nuclei exhibiting shape coexistence [6], can only occur via E0 transitions, i.e. via internal conversion electron emission.

Core temperature (T(C)) is a critical determinant of the severity of neural damage that results from focal or global ischemia. Former studies indicated that especially intra‐ischemic but also post ischemic mild hypothermia significantly decreased necrotic neural damage of a focal or global insult, as assessed between 3–7 days post‐insult. More recent work shows that prolonged post‐ischemic hypothermia reduces neural damage and inhibits associated behavioral deficits for up to one year after the insult (i.e. true neuroprotection with behavioral preservation). Alternatively, increases in core temperature via external heating or with pyrogens resulting from bacterial infections, at the time of the global ischemia insult worsen the neural damage of ischemic animals from those of respective normothermic controls given the same insult. This is paralleled in the clinical setting whereby ∼50% of ischemic patients develop fevers within 2 days of the insult and have worsened neurological outcomes than non‐febrile patients. The review discusses the possible mechanisms of neuroprotection of hypothermic therapy from cerebral ischemia as well as mechanisms involved in the exacerbation of neural damage of hypoxic ischemia under hyperthermic conditions. Questions are raised as to whether the medical community has sufficient evidence to begin appropriate hypothermic therapy of acute stroke patients. The importance of accurate monitoring core temperatures of all suspected stroke patients is emphasized, noting the differences in temperature that can occur with age, sex, medication or lifestyle so that appropriate temperature treatment could be implemented, if required. A. Hypothermia and cerebral ischemia

The enzymatic activity of endothelin-converting enzymes (ECE) was altered to determine the potential effect of endothelins (ET) on cerebral blood flow measured by laser Doppler flowmetry (CBF LDF ) and the resultant neural damage of rats, made hypoxic via breathing 12% O 2 for 35 min. Intrastriatal administration of phosphoramidon (PRN, 5 μM), a dual inhibitor of ECE and neutral endopeptidase (NEP), significantly increased infarct volume to hypoxia with a significant attenuation of CBF LDF . However, intrastriatal thiorphan (TRN, 5 μM), an inhibitor of NEP, had no effect on the CBF LDF responses or infarct volume induced by the hypoxic challenge. These findings showed that inhibition of ECE by PRN interfered with the vasodilator activity of ET to the hypoxic response that increased neural damage, thus suggesting that PRN-sensitive ECE is functionally active in the modulation of cerebral blood flow in rats undergoing hypoxia.

Experiments were conducted to compare the impact of febrile versus nonfebrile lipopolysaccharide (LPS) induced bacterial infection at the time of global hemispheric hypoxic ischemia (GHHI) on the neural damage evoked by the GHHI insult. In the first study acute intraperitoneal (i.p.) sterile saline (SS) or LPS Escherichia coli (60 µg/kg) was given to groups of male, conscious Long Evans rats, and core (colonic, Tc) temperatures were monitored over 6 h postinjection. Peak febrile response occurred ~5 h after the LPS E. coli was injected. Upon sacrifice 7 days later, no hemispheric or regional brain damage occurred in the saline or LPS-injected groups of this first study. In the second study, GHHI was applied (ligation of right common carotid artery + 35 min of 12% O2) in groups of anesthetized, male Long Evans rats previously given an acute i.p. injection of sterile saline or 60 µg/kg LPS E. coli 5 h earlier. Temperatures (Tc) were monitored before, during, and 1.5 and 24 h following GHHI. The LPS-injected group was subdivided into a febrile (Tc > 38°C before and (or) after GHHI) and nonfebrile (Tc < 38°C before and after GHHI) subgroups. A significant correlation was found between the peak temperature rise from preinjection control values following drug administration of either saline or LPS E. coli and the resultant hemispheric damage caused by GHHI. Moreover, upon sacrifice 7 days later ipsilateral hemispheric and regional (i.e., hippocampal, thalamic) damage to GHHI of the febrile LPS E. coli group was significantly increased from respective hemispheric, hippocampal, and thalamic damage of the saline and nonfebrile, LPS groups given the same ischemic insult. Results suggest that the heightened Tc of a LPS infection at the time of global ischemia exacerbated the neural damage of GHHI, a finding similar to that reported with heightened core temperatures induced by external heating.Key words: febrile infection, stroke, temperature, neural damage.

This study was designed to determine if central (intracerebroventricular, i.c.v.) administration of prostaglandin E2 (PGE2, mediator of core temperature elevation following exogenous or endogenous pyrogen administration) worsens the neural damage of anesthetized rats to global hemispheric hypoxic-ischemia (GHHI) from damage seen in normothermic, i.c.v. saline control groups. The first study (no GHHI) showed that 10 or 50 ng PGE2 given i.c.v. to groups of anesthetized Long–Evans rats evoked dose-related increases in colonic (systemic core) temperature but no neural damage. In the second study anesthetized rats were given an i.c.v. injection of sterile saline or PGE2 plus GHHI (ligation of the right common carotid artery plus 35 min of 12% O2) at the peak of the temperature response. Thermal response indices (TRI, °C×min), determined from brain (temporalis muscle, ipsilateral and contralateral to ligation) and core (colonic) temperatures, showed significant increases in the 50-ng PGE2 group compared to the TRIs of the 10-ng PGE2 or saline control group. The 50-ng PGE2, GHHI group had a higher mortality rate and showed greater ipsilateral hemispheric neural damage than the saline-treated group given the same insult, especially due to increased damage to the cortex. The results show that i.c.v. PGE2 administration significantly increases the neural damage caused by GHHI, possibly due to the associated rise in core temperature.

The present study was designed (1) to determine if scrotal thermal stimulation would activate brown adipose tissue (BAT) thermogenesis, indicated by increases in interscapular BAT temperature (TIBAT) of cold acclimatized (CA, kept at 4 degrees C for 4 weeks) and room temperature acclimatized rats (RA, kept at 21 degrees C for 4 weeks) and (2) to compare the thermoresponsiveness of VMH neurons of both groups to scrotal heating and cooling. VMH extracellular activity was recorded in male RA and CA Sprague-Dawley rats when scrotal temperatures (Tsc) were changed between 5-40 degrees C via localized thermode (3 mm2) along with measurements of TscS and TIBATS. The CA-group showed significant increases in TIBATS during scrotal cooling compared to respective TIBATS of the RA-group. The ratio of VMH warm responsive (WRN), cold responsive (CRN) and temperature non-responsive (TNRN) neurons in the CA-group changed compared to that in the RA-group as a greater percentage of CRNs occurred in the CA-group. Also, the thermoresponsiveness of individual VMH CRNs of the CA rats was significantly increased compared to VMH CRNs of the RA-group. The results indicated that localized scrotal cooling of CA-rats (not RA-rats) can activate BAT thermogenesis. Furthermore, VMH CRNs increased their thermoresponsiveness with chronic cold exposure which may be an important neuronal adaptive response for the subsequent enhanced BAT thermogenic effector response seen in that group.

Stroke occurs in all age groups, ranging from the new-born to the elderly. Our current understanding of the mechanisms of ischemic brain injury suggests that, despite age, the underlying cascade of events includes the rapid depletion of energy reserves, lactate accumulation, release of excitatory amino acids, high intracellular concentrations of Ca2+, and the production of oxygen free radicals. The extent to which these events affect brain injury, however, is profoundly influenced by age. Hyperglycemia for example, markedly enhances hypoxic-ischemic brain damage in adults, but has a protective effect in new-born rats. Insulin-induced hypoglycemia, on the other hand, protects the adult brain, but may be detrimental to the new-born. Substrate utilization of ketone bodies is markedly enhanced in the new-born, and has now been shown also to protect the brain. The immature brain is generally believed to be more resistant to the damaging effects of cerebrovascular compromise compared to the more mature brain. However, recent experiments suggest that the correlation between brain damage and age is not linear. To further clarify the effects of age and development on hypoxic-ischemic brain damage, we developed a model whereby rats of increasing age received identical cerebrovascular insults. Neuropathologic assessment at 7 days of recovery showed that brain damage was most severe in the 1- and 3-week-old animals followed by those that were 6 months. The 6- and 9-week-old groups had significantly less injury than the other three age groups. Hippocampal damage was most severe in the 3-week and 6-month-old rats compared to all other age groups. These findings contrast previously held beliefs regarding the enhanced tolerance of the immature brain to hypoxic-ischemic damage and demonstrate that the immature brain is, in fact, less resistant to hypoxic-ischemic brain damage than its adult counterpart. The results emphasize the need for a greater understanding of the effects of ontogeny on hypoxic-ischemic brain damage, particularly as it pertains to the development of therapeutic interventions.

Thermoresponsiveness of ventromedial hypothalamic (VMH) neurons to scrotal thermal stimulation was determined before and after microinjection of lidocaine into the medial preoptic nucleus (MPO). Male, urethane anesthetized Sprague-Dawley rats, maintained colonically at 37 degrees C had VMH extracellular neuronal activity recorded following 3 cycles of scrotal thermal stimulation (localized, incremental heating and cooling, between 10 and 40 degrees C). Based on their thermal coefficients (TC), warm (WRN), cold (CRN) thermoresponsive and temperature non-responsive (TNRN) VMH neurons had their neuronal activity recorded following each cycle of scrotal thermal stimulation before and after MPO injections of sterile saline (300 nl volume) or 2% buffered lidocaine (200 ng). Thermoresponsiveness of all warm and cold VMH neurons to scrotal thermal stimulation was blocked by prior lidocaine administration into the MPO, effects that were reversed approximately 60 min after. However, MPO lidocaine administration caused no significant change in the thermal coefficients of VMH TNRNs to scrotal thermal stimulation. Results infer that a functional MPO is required for thermal afferent signals arising from the scrotum to reach thermoresponsive VMH neurons.

Experiments were designed to determine if a functional ventromedial hypothalamic nucleus was required for the activation of brown adipose tissue thermogenesis evoked by medial preoptic stimulation. Male, urethane-anesthetized Long–Evans rats, maintained at 37 °C, had temperatures (thermistor probes for gastrocnemius, Tm; intrascapular brown adipose tissue, 7IBAT; colonic, Tc; and tail, Tt), gastrocnemius electromyogram activity (via stainless steel recording electrodes), and systemic blood pressure and heart rate (via a femoral arterial catheter) measured before and after a series of unilateral medial preoptic electrical stimulations (monophasic 0.5-ms pulses of 300 μA at 50 Hz for 30 s). Measurements were made (i) after an initial control medial preoptic electrical stimulation, (ii) after medial preoptic stimulation was applied 1 min following an intracranial injection of 300 nL of sterile saline or buffered 2% Lidocaine into the ipsilateral posterior hypothalamic nucleus or the ipsilateral ventromedial hypothalamic nucleus, and (iii) after recovery medial preoptic stimulation 45 min after Lidocaine was injected into the ventromedial hypothalamic nucleus. TIBAT and blood pressure rose significantly (p m and Tt did not significantly change from the corresponding prestimulation values. A recovery medial preoptic stimulation 45 min after Lidocaine treatment of the ventromedial hypothalamic nucleus again evoked significant increases in TIBAT above the core temperature, similar to the rise in TIBAT seen after the first control medial preoptic stimulation. Pretreatment with Lidocaine into the posterior hypothalamic nucleus before medial preoptic stimulation caused no suppression of blood pressure compared with treatments after the control medial preoptic stimulation; however, TIBAT was reduced (p IBAT seen after the control stimulation. Results indicate that a functional ventromedial hypothalamic nucleus is required for medial preoptic stimulation to activate brown adipose tissue thermogenesis.Key words: brown adipose tissue thermogenesis, medial preoptic stimulation, thermoregulation, heat production.

Experiments were conducted to determine whether ventromedial hypothalamic (VMH) neurons were responsive to thermal warming or cooling of the scrotum. Extracellular neuronal activity of VMH neurons was monitored in anesthetized groups of normothermic (core temperature maintained at 37 °C) or hypothermic (core temperatures allowed to decrease, 33.3 ± 1.1 °C) male, Sprague–Dawley rats along with colonic (Tc), interscapular brown adipose tissue (TIBAT), tail (Tt), and scrotal (Tsc) temperatures during 30-min periods of scrotal cooling (small ice pack) or scrotal warming (small sealed pack containing 40 °C tap water). In the normothermic group (65 VMH neurons recorded in total), 20 VMH neurons (31%) were classified as warm-responsive neurons (WRNs) (i.e., increased firing rate with scrotal warming and (or) decreased firing rates with scrotal cooling); 7 VMH neurons (11%) were classified as cold-responsive neurons (CRNs) (i.e., increased firing rate with scrotal cooling and (or) decreased firing rate with scrotal warming); and 38 VMH neurons (58%) were thermal nonresponsive neurons (TNRNs). In the hypothermic group (total of 85 VMH neurons recorded), 14 neurons (16%) were WRNs, 15 neurons (18%) were CRNs, and 56 neurons (66%) were TNRNs. Results indicated that VMH neurons can respond selectively to changes in scrotal temperature, as previously shown for preoptic–anterior hypothalamic neurons. Scrotal cooling and warming caused marked changes in T(sc) values in both the hypothermic and normothermic rats, but significant increases in TIBAT values indicative of brown adipose tissue thermogenesis did not occur.Key words: ventromedial hypothalamic nucleus, extracellular neuronal recording, temperature, scrotum.

Venous capacitance plays an important role in cardiovascular homeostasis. The anatomical loci within the central nervous system involved in modulating venous function remain to be elucidated. Stimulation of the hypothalamic paraventricular nucleus is known to increase sympathoadrenal outflow and arterial blood pressure. The present study was undertaken to determine whether electrical stimulation of the paraventricular nucleus can also affect the venous circulation. Mean circulatory filling pressure (MCFP) was used as an index of venous tone. Male Long Evans rats were initially anesthetized with pentobarbital (i.p.; 60 mg/kg) and subsequently maintained with urethane (i.v.; 600 mg/kg). Blood pressure and systemic venous pressure were monitored via catheters in the femoral artery and vein and heart rate eas derived from the pulsatile blood pressure signal. A latex tipped balloon was placed in the right atrium via the right jugular vien. Mean circulatory filling pressure was calculated from the arterial and venous plateau pressures recorded during five second balloon inflations. Arterial pressure, systemic venous pressure, heart rate and mean circulatory filling pressure were monitored before and during unilateral monopolar electrical stimulation (0.5 ms pulses at 50 Hz for a train duration of 10 s with constant current intensities of 100, 150, 200, and 300 μA) of the paraventricular nucleus. Increased graded stimulation of the paraventricular nucleus increased blood pressure by 6 ± 2, 8 ± 1, 13 ± 2 and 26 ± 5 mm Hg while heart rate changed by −22 ± 6, −18 ± 6 and −15 ± 9 bpm and+10 ± 10 bpm, respectively. Moreover, graded increases in MCFP of 0.64 ± 0.09, 1.04 ± 0.21, 1.19 ± 0.11 and 1.50 ± 0.25 mm Hg were observed concurrently. The results demonstrate, for the first time, that in addition to the documented effects on the arterial circulation, stimulation of the paraventricular nucleus induces systemic venoconstriction.

A simple, inexpensive computer interface designed for in vitro or in vivo researchers with limited electronic experience allows direct on-line multi-channel temperature recording from thermistor probes to any micro-computer. The designed system saves time and increases the accuracy of collected data that are ready for storage in files compatible with graphic and statistical software. In vitro testing of the designed interface, over a range of 25–45°C, showed a 0.999 intraclass correlation to reference water bath temperatures. In vivo testing using anesthetized rats involved simultaneous measurements of: (1) a thermogenic tissue, interscapular brown adipose temperature (IBAT), (2) core (colonic) temperature, and (3) surface (tail) temperature, a heat loss tissue. The temperatures measured by the designed computer-interface demonstrate excellent stability, sensitivity and accuracy when compared to respective temperatures measured by a YSI telethermometer.

Experiments were conducted to determine if both electrical and chemical stimulation of the ventromedial hypathalamic nucleus (VMH) could activate brown adipose tissue (BAT) thermogenesis. Age-matched, room-acclimated (21 °C) and cold-acclimated (4 °C for 3 weeks prior to testing) male Sprague-Dawley rats were given unilateral electrical or chemical stimulation to the VMH by way of a ‘chemotrode apparatus’. The devised ‘chemotrode’ allowed both electrical stimulation (insulated piano wire stimulating electrode) and chemical stimulation (23 gauge stainless steel intracranial cannula of equal length) to be performed at the same VMH site using a common 19 gauge stainless steel outer guide tube. The first unilateral VMH electrical stimulation (0.5 ms pulse, 50 Hz and 120 μA for 30 s) caused no significant rise in interscapular brown adipose tissue temperature (Tbat) colonic (Tc) or tail surface temperatures (Tt), compared to respective prestimulation control values in rats acclimated to 21 °C. In the 4 °C-acclimated group the first VMH electrical stimulation caused a significant rise in IBAT temperature.l-Glutamate administration to the same VMH site (60 nmol in 600 nl volume) also caused a significant increase in IBAT temperature in the 4 °C but not the 21 °C-acclimated rats. The rise in IBAT temperature following thel-glutamate injection to the 4 °C-acclimated group was similar to that found following the first electrical stimulation to this group. Interestingly, a second unilateral electrical stimulation of the VMH to 4 °C-acclimated rats could not evoke a similar increase in IBAT temperature suggesting that overalll-glutamate was acting in vivo as an excitotoxin. The results indicate that both unilateral chemical and electrical stimulation of the VMH of 4 °C but not 21 °C acclimated, anesthetized male Sprague-Dawley rats can evoke significant rises in IBAT temperature, indicative of activation of BAT thermogenesis by this CNS site. These results infer that cold acclimation causes facilitation of BAT thermogenesis peripherally and/or centrally such that subsequent electrical or chemical stimulation of the VMH can then evoke significant rises in IBAT temperature in those animals.

Experiments were conducted (i) to determine the hemodynamic (blood pressure and heart rate) responses of conscious rats following intrathecal (IT) administration of endogenous prodynorphin-derived opioids into the lower thoracic space, (ii) to identify the receptors involved in mediating their cardiovascular responses, and (iii) to reveal any possible hemodynamic interactions with the neuropeptide arginine vasopressin. Male Sprague–Dawley rats were surgically prepared with femoral arterial and venous catheters as well as a spinal catheter (into lower thoracic region, T9–T12). After recovery, hemodynamic responses were observed in conscious rats for 5 – 10 min after IT injections of artificial cerebrospinal fluid (CSF) solution, prodynorphin-derived opioids (dynorphin A, dynorphin B, dynorphin A (1 – 13), dynorphin A (1 – 10), α- and β-neoendorphin, leucine enkephalin (LE), methionine enkephalin (ME), arginine vasopressin (AVP), or norepinephrine (NE)). IT injections of AVP (10 or 20 pmol), dynorphin A (1 – 13), or dynorphin A (10 – 20 nmol) caused pressor effects associated with a prolonged and significant bradycardia. Equimolar (20 nmol) concentrations of LE, ME, α- and β-neoendorphin, and dynorphin A (1 – 10) caused no significant blood pressure or heart rate changes. Combined IT injections of dynorphin A (1 – 13) and AVP caused apparent additive pressor effects when compared with the same dose of either peptide given alone. IT infusion of the specific AVP–V1 antagonist d(CH2)5Tyr(Me)AVP before subsequent IT AVP, dynorphin A (1 – 13), or NE administration inhibited only the subsequent pressor responses to AVP. The x-opioid antagonist (Mr2266) infused IT blocked the pressor actions of subsequent dynorphin A administration and not AVP or NE. These results indicate that dynorphin A and dynorphin A (1 – 13), in the doses used, given IT to conscious rats evoked pressor and bradycardic responses. The pressor actions of dynorphin A appear to be mediated by spinal x-opioid receptors and are independent of interaction with spinal AVP–V1 receptors.Key words: prodynorphin-derived peptides, arginine vasopressin, intrathecal administration, hemodynamic effects, specific receptor-mediated responses.

Brain temperature is an important variable in determining the outcome of cerebral ischemia; increases in core temperature escalate neural damage whereas decreases in core temperature reduce damage. Fever induction often occurs in patients prior to or as a direct or indirect result of the ischemic insult, with a worsened stroke outcome, compared with non-febrile ischemic patients. Most importantly, post-ischemic hypothermia reduces long term neural damage and associated behavioral deficits in animals studied for up to a year after the ischemic insult. This review discusses the importance of monitoring the brain temperature of stroke patients and implemention of therapeutic thermoregulatory strategies to reduce the temperature of ischemic patients.Key words: hypothermia, neuroprotection, fever, neural and behavioral outcomes.

Levels of endothelin-1 (ET-1), a potent endogenous vasoconstrictor, are elevated in plasma and cerebrospinal fluid (CSF) following cerebral ischemia and reperfusion injury. The present study sought insight into the potential differential vasoactive effects on the cerebral vasculature and resultant neural damage of ET-1 during normoxic vs. ischemic conditions and upon reperfusion. Under normoxic conditions, intrastriatal stereotaxic injection of exogenous ET-1 (40 pmol) induced a significant (P0.05) reduction (/=29+/-12%) in the regional (striatal) cerebral blood flow measured by Laser Doppler flowmetry (CBF(LDF)) for up to 40 min in halothane-anesthetized male Long-Evans rats. Intrastriatal injection of ET-1 10 min after the onset of hypoxia (12% O(2), balance N(2)) tended to blunt, but not significantly, the striatal CBF(LDF) responses to the 35 min period of hypoxia. ET-1 given during reoxygenation significantly (P0.05) reduced striatal CBF(LDF), which was similar to the effect of ET-1 during normoxia. ET-1-induced infarction when administered prior to hypoxia, but not during or post-hypoxia, was significantly (P0.05) exacerbated compared to infarction of ET-1 without hypoxia. These results suggest that exogenous ET-1 administered into the brain parenchyma can induce an infarction associated with modulation of CBF(LDF) during the normoxic or reoxygenation period, but not during the hypoxic period and that the increased release of ET-1 in any pathological phase of cerebral ischemia contributes to irreversible neural damage with associated hemodynamic disturbances.

Athletic animals must keep their brains cool during exertion because this organ can be damaged irreversibly by hyperthermia. But how horses do this has remained a mystery, as they don't appear to have thermoregulatory dervices like those found in other animals. They do, however, have a unique anatomical arrangement of their internal carotid arteries, which supply blood to the brain: these are enveloped by a pair of air-filled guttural pouches. Here we show that horses use their guttural pouches to cool these important arteries during exercise, keeping the brain from overheating.

The study determined if head cooling would reduce the augmented increase in neural damage of global hemispheric hypoxic ischemia (GHHI) of prostaglandin E2 (PGE2) treated rats. Halothane anesthetized, male, Long-Evans rats (9-11 weeks of age), kept at 37 degrees C colonically (Tc) had (a) systemic core (colonic, Tc), temporalis muscle temperatures ipsilateral (Tipsi) and contralateral (Tcontra) to the side of right common carotid artery (RCCA) ligation, (b) mean arterial pressure (MAP) and (c) ipsilateral cortical capillary blood flow (CBF) measured simultaneously after intracerebroventricular (i.c.v.) injection (2.5 microl) of sterile (SS) or 25 ng PGE2 then GHHI (35 min of 12% O2, balance N2 after RCCA ligation) followed by a 10 min normoxic recovery period. Head cooling (10 degrees C cool air over the head region) occurred in one PGE2 subgroup 10 min post-injection until the end of the hypoxic period. Icv-PGE2 treated rats, maintained at 37 degrees C (no head cooling) had increased Tc, Tipsi, Tcontras and MAPs from respective pre-injection control values; this group showed increased ipsilateral hemispheric neural damage to GHHI assessed 7 days later, compared to i.c.v.-SS treated group given the same GHHI insult. Cooling the head region of rats previously given PGE2 decreased Tipsi and Tcontras from respective control temperatures but did not change MAP or CBF from respective pre-injection values. Hemispheric damage of the PGE2 cooled group was reduced from damage of non-cooled PGE2 treated rats and was similar to i.c.v.-SS treated rats. Results demonstrate that the heightened core temperatures induced by PGE2 administration (major endogenous mediator of bacterial fever induction) play a significant role in escalating the neural damage to global ischemia.

The thermoresponsiveness of posterior hypothalamic (PH) neurons to localized, incremental thermal heating and cooling between 10-40 degrees C of the abdomen or scrotum was determined in urethane anesthetized, male Sprague-Dawley rats whose core temperature was maintained at 37 degrees C during testing. PH extracellular neuronal activity was recorded along with changes in gastrocnemius muscle EMG activity and temperature (Tms, indicative of shivering thermogenesis) and intrascapular brown adipose tissue temperature (TIBATs, indicative of non-shivering thermogenesis). Seventy-five PH neurons were recorded following both scrotal and abdominal trials of thermal stimulation. Nine percent of PH neurons were classified as warm responsive neurons (WRNs), 20% as cold responsive (CRNs), and 71% as temperature nonresponsive neurons (TNRNs), based on their thermal coefficients (TCs). Mean TC for warm PH neurons was significantly increased with scrotal warming between 30-40 degrees C from the mean TC of the same PH WRNs following abdominal warming. Similarly, the thermal coefficient was increased (i.e., was more negative) for cold responsive PH neurons to scrotal cooling (20-10 degrees C) as opposed to the TC of the same PH CRNs for abdominal cooling. No shivering thermogenesis (no change in temperature or EMG activity from gastrocnemius muscle) or non-shivering thermogenesis (no significant increase in IBAT temperatures) occurred with scrotal or abdominal cooling in these 21 degrees C acclimatized rats. The results indicate that a small population of PH neurons are thermoresponsive to localized physiological changes in temperature of the scrotum and abdomen with greater thermoresponsiveness shown of both warm and cold PH neurons to scrotal vs. abdominal thermal stimulation.

Neurons within the central nervous system, including those within the ventromedial hypothalamic (VMH) nucleus, alter their neuronal activity in response to scrotal thermal stimulation. This study set out to establish if the thermoresponsiveness of VMH neurons becomes modified to repeated trials of scrotal thermal stimulation. VMH extracellular activity was recorded with a glass micropipette filled with 0.5 M sodium acetate in urethane-anaesthetized male Sprague-Dawley rats following 20 min scrotal heating (scrotal packs, 2 x 2 cm, filled with 40 degrees C hot water) and scrotal cooling (scrotal packs filled with ice). In study A, VMH neurons were tested to 2 trials of scrotal heating and cooling with colonic temperatures (T(c)s) servo-controlled at 37 degrees C during both trials. In study B, VMH neurons were tested for 3 trials of scrotal thermal stimulation, with T(c)s servo-controlled at 37, 35 and 33 degrees C during the 3 trials. In study A, 42 VMH neurons were isolated. Based on their thermal coefficients (TCs) to the 1st trial of scrotal heating and cooling, 12 VMH neurons were classified as warm-responsive neurons (WRNs), 10 as cold-responsive neurons (CRNs) and 20 were temperature-non-responsive neurons (TNRNs). Of the neurons recorded long enough to test their thermoresponsiveness to 2nd trial of scrotal thermal stimulation (9 out of 12 WRNs, 7 out of 10 CRNs and 18 out of 20 TNRNs), the mean TCs of each type of VMH neuron did not significantly change between the 2 trials. In study B, 65 VMH neurons were isolated and 11 out of 22 WRNs, 7 out of 13 CRNs and 15 out of 30 TNRNs had their thermoresponsiveness tested to 3 trials of scrotal heating and cooling, with T(c)s kept at 37, 35 and 33 degrees C, respectively, for these trials. The mean TCs for VMH WRNs, CRNs and TNRNs again did not change between the 3 trials of scrotal thermal stimulation. However, mean basal firing rates did increase significantly of all recorded VMH neurons between the 1st and 3rd trials of scrotal heating and cooling as T(c)s were acutely lowered from 37 to 33 degrees C. Results demonstrated that VMH thermoresponsive neurons retain their responsiveness to repeated trials of scrotal heating and cooling of animals maintained at normothermic (37 degrees C) or acutely hypothermic (35 and 33 degrees C) temperatures.

Stroke occurs in all age groups, ranging from the newborn to the elderly. The immature brain is generally believed to be more resistant to the damaging effects of cerebrovascular compromise compared to the more mature brain. However, recent experiments suggest that the correlation between brain damage and age is not linear. To determine the effects of age and development on hypoxic-ischemic brain damage, we developed a model whereby rats of increasing age received identical cerebrovascular insults, and assessed neuropathologic outcome. Male Wistar rats of 1, 3, 6, and 9 weeks and 6 months underwent unilateral common carotid artery ligation and exposure to 12% oxygen for 35 min. Animals were all spontaneously breathing under light halothane anesthesia (0.5%). Core temperatures were maintained at 37 degrees C. Blood pressures were monitored via indwelling carotid artery catheters on the side ipsilateral to the carotid artery ligation. Cerebral blood flow was assessed in separate groups utilizing Laser Doppler flowmetry. Physiologic monitoring revealed that under these experimental conditions, mean arterial blood pressure and cerebral blood flow decreased to the same extent in each of the age groups, verifying that all animals experienced an identical insult. Neuropathologic assessment at 7 days of recovery showed that brain damage was most severe in the 1 and 3 week old animals followed by those that were 6 months. The 6 and 9 week old groups had significantly less injury than the other 3 age groups. Hippocampal damage was most severe in the 3 week and 6 month old rats compared to all other age groups. Our findings contrast previously held beliefs regarding the enhanced tolerance of the immature brain to hypoxic-ischemic damage and demonstrates that, in a physiologically controlled in vivo model of hemispheric global ischemia, (1) the immature brain is, in fact, less resistant to hypoxic-ischemic brain damage than its adult counterpart, (2) the brain damaging effects of hypoxic-ischemia are age dependent, but do not increase linearly with advancing age and development, and (3) the intermediate age groups are more tolerant to hypoxic-ischemic brain injury than either very young or more mature ages.

Experiments were conducted to determine if the area of stimulation within the preoptic area and/or the magnitude of the electrical stimulus applied to the preoptic region would selectively alter the evoked thermogenic responses of normothermic and hypothermic rats. Urethane anesthetized male, Long-Evans rats kept at 37°C, and later cooled to 34°C, were given unilateral electrical stimulation (0.5 ms pulses of 200 μA at 50 Hz for 30 and 300 s) into either the medial preoptic area (MPO) or the lateral preoptic area (LPO). Temperature changes of intrascapular brown adipose tissue, T IBAT s; of gastrocnemius muscle, T m s, tail, T t s and colonic T c s via thermistor probes were recorded before and after stimulation along with differential, multi-unit EMG activity of the gastrocnemius muscle via implanted stainless steel electrodes. The group kept at 37°C and given MPO electrical stimulations evoked graded increases in T IBAT s above core dependent on the duration of the electrical stimulus but shivering did not occur and T m s did not rise. When kept at 34°C the MPO-stimulated group showed greater increases in T IBAT s than respective reponses seen when the same stimuli were applied at 37°C. The group maintained at 37°C and given LPO stimuli over 300 s increased T m s as shivering occurred, yet no change in T IBAT s were observed. When cooled to 34°C LPO stimulation (30 or 300 s duration) showed greater shivering activity. Interesting, LPO stimulation of animals maintained at 34°C also caused T IBAT to increase. Results indicate that electrical stimulation of the preoptic area of anesthetized rats kept at 37°C can activate specific thermogenic effector responses, as MPO stimulation elicits BAT thermogenesis whereas LPO stimulation evokes shivering thermogenesis. With rats kept at hypothermic T c s, LPO and MPO stimulation cause greater shivering and BAT thermogenesis, respectively than those seen within each group when tested at 37°C; in addition, either LPO or MPO stimulation also activated the other thermogenic effector.

Experiments were designed to determine in the same animal whether electrical stimulation of the posterior hypothalamus and ventromedial hypothalamic nucleus could specifically evoke shivering and nonshivering (brown adipose tissue) thermogenesis, respectively, in anesthetized, normothermic rats. Urethane-anesthetized, male Long–Evans rats, kept at 37 °C, had colonic (Tc), gastrocnemius muscle (Tm), intrascapular brown adipose tissue (TIBAT), and tail (Tt) temperatures measured via thermistor probes, and electromyogram activity (differential multiunit activity from bipolar recording electrodes within gastrocnemius muscle) recorded, before and after unilateral electrical stimulation (monophasic 0.5-ms pulses of 200 μA at 50 Hz for 30 s) of the posterior hypothalamus and ventromedial hypothalamic nucleus (via stereotaxically implanted concentric stimulating electrodes). Each rat showed shivering (increased electromyogram activity) following posterior hypothalamic stimulation, which caused an immediate rise in Tm values with no change in TIBAT or Tt values. Electrical stimulation of the ventromedial hypothalamic nucleus of the same animals elicited no shivering activity, but significant increases in TIBAT values occurred with no change in Tm or Tt values. Results confirm that stimulation of the posterior and ventromedial hypothalamic nuclei in rodents specifically activates shivering and nonshivering (brown adipose tissue) effector mechanisms, respectively, to raise core temperature.Key words: posterior hypothalamus, shivering thermogenesis, ventromedial hypothalamus, intrascapular brown adipose tissue thermogenesis.

Intrascapular brown adipose tissue temperature (TIBAT) and capillary blood flow along with colonic (Tc) and tail (Tt) temperatures as well as blood pressure and heart rate responses were measured simultaneously in groups of age-natched, anesthetised, sham control and IBAT-denervated Long-Evans rats following VNH electrical stimulation. Unilateral VMH electrical stimulation (0.5 ms pulses of 100 μA at 50 Hz for 30 s) evoked rises in TIBAT (above core) and IBAT blood flow in the Long-Evans sham control group, along with increases in blood pressure and heart rate. Rises in IBAT temperature and capillary blood flow were absent in the surgical denervated group following VMH electrical stimulation whereas the evoked pressor and tachycardic responses were left intact and were similar to those responses seen in the sham control group. The results indicate that acute bilateral sectioning of the IBAT intercostal nerves blocks the IBAT temperature and capillary blood flow increases evoked by VMH electrical stimulation.

Normothermic (37 degrees C), anesthetized Long Evans rats given unilateral electrical stimulation (0.5 ms monophasic pulses of 100-300 microA at 50 Hz for 30 s) of the posterior hypothalamus (PH) had graded, sustained increases in EMG electrical activity of the gastrocnemius muscle (i.e. shivering). In a current-related manner, gastrocnemius muscle temperatures (Tm) immediately increased following PH stimulation, surface temperatures (Tt) did not change and colonic (core, Tc) temperatures initially fell, then subsequently rose after the applied stimulus. A biphasic pressor response occurred after PH electrical stimulation associated with tachycardia. PH electrical stimulation (0.5 ms pulses at 50 Hz for 30 s of only 40 microA) induced shivering in anaesthetized, hypothermic Long Evans rats undergoing acute cold exposure. When these same hypothermic rats were cooled further to cause shivering, PH electrical stimulation (0.5 ms pulses at 50 Hz for 30 s of only 40 microA) induced further increases in the shivering response (increases EMG area of gastrocnemius muscle) from the shivering response before PH stimulation. Results indicate that electrical stimulation of the PH can evoke shivering in anesthetized normothermic rats. Stimulation of the PH with lower current intensity can induce or increase shivering of hypothermic rats previously exposed to the cold.

Thermoregulatory (brown adipose tissue temperature) experiments were conducted in age-matched anesthetized, male Sprague-Dawley and Long Evans rats kept at 37 degrees C given unilateral electrical stimulation of the ventromedial hypothalamic nucleus or the lateral preoptic area or after intravenous infusion of norepinephrine HCl (50 micrograms/kg total dose). Unilateral electrical stimulation (0.5 ms pulses of 250 microA at 50 Hz for 30 s) of the ventromedial nucleus or lateral preoptic area caused significant rises (greater than 0.6 degrees C) of intrascapular brown adipose tissue temperature in the Long Evans group only. Norepinephrine infusion (0.1 ml/min for 10 min), or intravenous bolus injection of propranolol HCl (2.5 mg/kg) caused significant yet similar increases (greater than 1.0 degrees C) and decreases (greater than -0.3 degrees C), respectively, of intrascapular brown adipose tissue temperature from pre-administration control temperatures in both Long Evans and Sprague-Dawley groups. The results demonstrate that intrascapular brown adipose tissue sensitivity towards exogenous norepinephrine or propranolol administration is similar between Sprague-Dawley and Long Evans rats acclimated to 21 degrees C as determined by increases in temperature in the intrascapular brown adipose tissue pad. However, intrascapular brown adipose tissue thermogenesis of 21 degrees C-acclimated Long Evans rats is also activated after CNS electrical stimulation of the ventromedial nucleus or lateral preoptic area, an activation not seen in Sprague-Dawley rats suggestive that the latter group has some inhibition of neural pathways that activate brown adipose tissue thermogenesis.

The designed inexpensive blood pressure recording system (BPRS) gives any microcomputer direct on-line blood pressure and heart rate recording capability that will save research time and increase the accuracy of collected data. The data is automatically stored in a file compatible with most graphic and statistical processing software. In vitro testing, over a range of 0-200 mmHg and 0-360 beats per minute showed a 0.999 intraclass correlation. In vivo testing of the BPRS used anaesthetized rats whereby their systolic and diastolic pressures were measured simultaneously with heart rate. The blood pressures and heart rate data, measured by the BPRS demonstrated excellent stability, sensitivity and accuracy when compared to those measured by standard pressure transducers in conjunction with a Grass polygraph and a sphygmomanometer.

Hemodynamic (blood pressure and heart rate) experiments were conducted in conscious and/or anesthetized male Sprague-Dawley (S.D.), heterozygous and homozygous Brattleboro rats given intravenous (iv) dynorphin A (1–13) , arginine vasopressin (AVP), norepinephrine HCl, (NE) or sterile saline before and 10 min after an iv bolus injection of a specific receptor antagonist. These receptor blockers (kappa receptor antagonist Mr2266, alpha adrenoceptor antagonist phentolamine HCl or the AVP-V 1 receptor antagonist d(CH 2 ) 5 Tyr-(Me)AVP were given in equimolar concentrations (15 nmol/kg iv). In all conscious S.D. groups, iv injection of AVP (60 pmol/kg), NE (12.5 nmol/kg) and dynorphin A (1–13) (60 nmol/kg) evoked significant increases in mean arterial pressure (MAP) associated with concomitant bradycardia. The hemodynamic responses to ‘both’ AVP and dynorphin A (1–13) were blocked if given subsequent to AVP-V 1 administration but not following phentolamine or Mr2266 pretreatment. The pressor and bradycardic responses of conscious heterozygous and homozygous Brattleboro rats after iv AVP or dynorphin again were only blocked by the AVP-V 1 receptor antagonist. Anesthetized heterozygous and homozygous Brattleboro rats again showed pressor responses following iv AVP, NE or dynorphin A (1–13) but with slight or no associated bradycardia. The rise in blood pressure with AVP ‘and’ dynorphin A (1–13) in these groups also was only blocked by the d(CH 2 ) 5 Tyr(Me)AVP antagonist. The results indicate that the pressor responses of rats given intravenous dynorphin A (1–13) involve the interaction of AVP-V 1 receptors and suggest a functional interaction of these two neuropeptides in the modulation of vascular tone.

1. Urethane-anaesthetized, age-matched cold-(4 degrees C) and room (21 degrees C)-acclimated groups of Sprague-Dawley rats were given repeated (three) ventromedial hypothalamic electrical stimulations. Interscapular brown adipose tissue (IBAT), colonic, surface tail temperatures and blood pressure were monitored before and after each electrical stimulation. Propranolol HCl (2.5 mg kg-1 i.v.) was given 10 min prior to the last (third) ventromedial hypothalamic stimulation. 2. Repeated electrical stimulation of the ventromedial hypothalamic (VMH) nucleus to either small or large rats (kept at 21 degrees C) caused no significant change in interscapular brown fat, colonic or surface temperatures compared to respective pre-stimulation control values whereas mean arterial pressure was slightly but significantly increased during the 30 s stimulation period. 3. Electrical stimulation of the ventromedial hypothalamic nucleus of small or large rats, kept at 4 degrees C for 3 weeks prior to testing, caused significant (greater than 0.25 and greater than 0.40 degrees C, respectively) rises in interscapular BAT temperature from respective prestimulation control values. Colonic temperatures increased following ventromedial hypothalamic electrical stimulation only in the small, 4 degrees C-acclimated group whereas surface tail temperatures did not significantly change after stimulation of either cold-exposed group. Mean arterial pressures were significantly increased during ventromedial hypothalamic electrical stimulation in both 4 degrees C-acclimated groups, compared to pre-stimulation control levels and, in addition, were above those of age-matched rats kept at 21 degrees C. Intravenous propranolol, which decreased interscapular brown fat and colonic temperatures in all groups, blocked the rise in interscapular brown fat and colonic temperatures of the 4 degrees C-acclimated rats following the last electrical stimulation of the ventromedial hypothalamic nucleus. 4. In vitro biochemical analysis of the interscapular brown fat pads of another four groups of age-matched, small and large 21 and 4 degrees C-acclimated rats revealed that the thermogenic capacity of the 4 degrees C-acclimated groups was, in all cases, significantly increased from age-matched groups previously kept at 21 degrees C, as shown by significant increases in brown adipose tissue mass, BAT DNA and protein content, BAT mitochondrial protein and BAT mitochondrial GDP binding.(ABSTRACT TRUNCATED AT 400 WORDS)

Experiments were conducted to determine (i) how naloxone administration alone could modify the inotropic (in electrically stimulated (ES) rat atria) and both the inotropic and chronotropic responses (in spontaneously beating (SB) rat atria) isolated from normotensive and hypotensive (hemorrhaged) rats, and (ii) how naloxone administration would modify the inotropic and chronotropic responses of isolated rat atria previously administered an opiate agonist (morphine), a muscarinic agonist (carbachol), or an α - and β-adrenergic agonist (noradrenaline). Naloxone (51–340 μM) added to ES atria caused a delayed but dose-related decrease in atrial tension (AT), whereas in SB atria, naloxone caused atrial heart rate (AHR) to fall and atrial tension (AT) to increase. Naloxone (68–340 μM), given to SB atria from acutely hypotensive rats, caused a similar increase in atrial tension as seen in the "normotensive" isolated (SB) atria and a similar decrease in atrial heart rate. Morphine sulphate (MS), 37–375 μM, administered to ES atria caused a delayed fall in AT, which was further decreased when naloxone (340 μM) was also added. In the SB atria, morphine caused a dose-related decrease in atrial heart rate whereas atrial tension increased. In SB preparations, atrial heart rate fell even further when naloxone was added to morphine compared with when morphine sulphate was given alone, whereas atrial tension was increased. Noradrenaline (3 or 12 μM) caused a positive, dose-related inotropic response in the ES atria, effects not influenced by the addition of naloxone. In the SB atria, naloxone caused no change in the dose-related increases in atrial tension and heart rate when combined with the lower dose of noradrenaline but decreased AT when combined with 12 μM noradrenaline, compared with when this dose of noradrenaline was given alone. Carbachol (683 nM – 1.37 μM) caused a dose-related decrease in atrial tension in ES atria, which was reversed completely by the addition of naloxone. In SB atria, carbachol decreased both atrial tension and heart rate, and with the addition of naloxone (340 μM), a further slight drop in atrial heart rate occurred, but concurrently, a marked rise in atrial tension was observed. The results indicate that naloxone can act with receptors directly within atrial tissue to cause changes in atrial tension and heart rate. The comparable delayed responses of morphine and naloxone suggest their effects are mediated by nonopiate receptors which, in time, cause decreases in calcium influx into the atria. The marked rise in atrial tension following naloxone administration in atria previously given carbachol suggest there is an interaction between naloxone- and carbachol-sensitive receptors in the atria. The net result of this interaction may again reflect a change (increase) in calcium influx into myocardial cells.Key words: rat atria, inotropy, chronotropy, morphine, carbachol, noradrenaline, acute hypotension.

The immature brain is believed to be more resistant to the damaging effects of H-I compared to the more mature brain. However, recent experiments suggest that the correlation between brain damage and age is not linear. To determine the effects of age and development on H-I brain damage, we developed a model whereby rats of increasing age received identical cerebrovascular insults, and assessed neuropathologic outcome. Male Wistar rats of 1, 3, 6, and 9 weeks and 6 months underwent unilateral common carotid artery ligation and exposure to 12% oxygen for 35 minutes. Animals were all spontaneously breathing under light halothane anesthesia (0.5%). Core temperatures were maintained at 37°C. Blood pressures were monitored via indwelling carotid or femoral catheters. Cerebral blood flow was assessed in separate groups utilizing Laser Doppler flowmetry. Physiologic monitoring revealed that under these experimental conditions, mean arterial blood pressure and cerebral blood flow decreased to the same extent in each of the age groups, verifying that all animals experienced an identical insult. Neuropathologic assessment at 7 days of recovery showed that brain damage was most severe in the 1 and 3 week old animals followed by those that were 6 months. The 6 and 9 week old groups had significantly less injury than the other 3 age groups. Hippocampal damage was most severe in the 3 week and 6 month old rats compared to all other age groups. Our findings contrast previously held beliefs regarding the enhanced tolerance of the immature brain to H-I damage and demonstrates that, in a physiologically controlled in vivo model of hemispheric global ischemia, 1) the immature brain is less resistant to H-I brain damage than it's adult counterpart, 2) the brain damaging effects of H-I are age dependent, but do not increase linearly with advancing age and development, and 3) intermediate age groups are most tolerant to H-I brain injury.

Experiments were designed using conscious Spargue–Dawley rats to determine the blood pressure (BP) and heart rate (HR) responses to intravenous doses of (1) the adrenal catecholamines noradrenaline (NA) and adrenaline (A), (2) adrenal pentapeptides methionine enkephalin (ME) and leucine enkephaline (LE), (3) combination (i.v.) injections of both ME or LE with NA or A that modulate the hemodynamic responses when the adrenal catecholamines were given alone, and (4) the possible receptor mechanisms mediating the resultant BP and HR response to i.v. pentapeptide administration. NA (0.48 and 2.4 nmol) and A (0.3 and 1.5 nmol) given i.v. evoked potent, dose-related pressor responses associated with reflex bradycardia. ME and LE (1.6 – 48 nmol) elicited transient (10–20 s) increases in mean arterial pressure (MAP), which was associated either with no change in mean heart rate (MHR), such as ME, or with slight bradycardia (i.e., LE). Combining ME or LE (16 nmol) with NA (2.4 nmol) or A (0.3 or 1.5 nmol) did not change MAP and MHR from when these respective doses of NA or A were given alone. However, 16 nmol of ME or LE with a low dose of NA (0.48 nmol) increased the pressor response compared with NA (0.48 nmol) given alone. Other experiments whereby specific receptor blockers (naloxone, diprenorphine, atropine, propranolol, phentolamine or quanethidine) were given i.v. 5 min before subsequent i.v. administration of LE or ME (16 nmol) indicated that only phentolamine or quanethidine could completely suppress the pressor responses of LE and ME. Naloxone and diprenorphine pretreatment attenuated the pressor response of LE but did not affect the BP response to ME. The results suggest that i.v. LE or ME injections to conscious rats evoke an α-adrenergic receptor-mediated pressor response which is not associated with tachycardia and that is likely due to vasoconstriction of the peripheral vasculature.

Hemodynamic (blood pressure and heart rate) responses of conscious drug-naive rats were studied following intravenous (i. v.) infusion of sterile saline, morphine sulphate, and then naloxone hydrochloride, as well as of other groups previously injected with morphine sulphate. Those groups chronically given morphine sulphate received twice daily injections of morphine sulphate (5 mg/kg, s.c. per injection) for 3 or 6 days before testing with the i. v. infusion of morphine sulphate. Drugs were infused (135 μL/min) through an indwelling femoral venous catheter via a Harvard infusion pump, and blood pressure was recorded from the abdominal aorta via a femoral arterial catheter. Other pretreatment studies were done to determine the receptor mechanisms mediating the blood pressure responses of drug-naive and chronic morphine-treated rats, whereby equimolar doses (0.32 μmol) of specific receptor antagonists were given as a bolus i.v. injection 5 min after saline but before subsequent infusion with morphine sulphate. Intravenous infusion of morphine sulphate (7.5 mg/kg total over 15 min) to drug-naive rats caused a transient but precipitous fall in mean arterial pressure and mean heart rate with an associated rise in mean pulse pressure; these effects were blocked in other groups pretreated with atropine. Interestingly, however, rats chronically injected with morphine sulphate for 3 days previously evoked a transient pressor response when subsequently infused i.v. with morphine sulphate, actions that were blocked in other groups when pretreated i.v. with 0.32 μmol of phentolamine, yohimbine, prazosin, or guanethidine. A greater and persistent pressor response occurred following morphine infusion to groups of rats previously injected over 6 days with morphine sulphate, which was associated with tachycardia during the later stages of the 15-min morphine sulphate infusion period. The prolonged pressor and tachycardic responses of this 6-day chronically injected group were completely blocked in another group pretreated i.v. with both phentolamine and propranolol (0.32 μmol). The results suggest that morphine sulphate infusion to conscious, drug-naive rats evokes classical hypotensive effects due to decreases in mean heart rate caused by activation of parasympathetic vagal activity. With 3 or 6 days of chronic morphine sulphate administration beforehand, subsequent i.v. infusion of morphine sulphate evoked pressor actions felt to be caused by a progressive activation of the sympathetic nervous system. These events cause vasoconstriction of peripheral vasculature and, with time, increased cardiac frequency, actions that can be blocked by pretreatment with specific α- and β-adrenergic receptor blockers.Key words: drug-naive rats, morphine-pretreated rats, acute hypotension, bradycardia, chronic pressor responses, opiate and non-opiate receptor blockade.

Experiments were designed to determine the hemodynamic responses of conscious, unrestrained rats given intracerebroventricular (i.c.v.) injections of dynorphin A-(1–13) and the possible central receptor mechanisms mediating those changes. Male Sprague-Dawley rats (300 g b. wt.) received i.c.v. injections (by gravity flow in a total volume of 3 or 5 μl) of control solutions of sterile saline (SS) or dimethylsulfoxide (DMSO) or 1.5, 3.0 or 6.1 nmol of dynorphin A-(1–13). Blood pressure and heart rate changes were monitored over 2 h after administration; as well, feeding activity was visually assessed and scored over this period. Other groups of conscious rats were pretreated i.c.v. with equimolar doses (3.0–24.4 nmol) of specific receptor antagonists (naloxone HCl, phentolamine HCl, propranolol HCl, yohimbine HCl or prazosin HCl) 10 min before subsequent i.c.v. administration of SS or DMSO/SS or 6.1 nmol of dynorphin A-(1–13). I.c.v. injection of dynorphin A-(1–13) caused a dose-related pressor response, associated temporally with tachycardia. As well, dynorphin evoked feeding activity and some grooming, which occurred when the rats were hypertensive and tachycardic and decreased as heart rate and blood pressure returned to control levels. I.c.v. pretreatment studies indicated that naloxone HCl (12.2 nmol), phentolamine HCl (12.2 nmol) and prazosin HCl (6.1 nmol) blocked the pressor response, tachycardia as well as feeding activity of rats subsequently given dynorphin. The results suggest the pressor and tachycardic effects of conscious rats following i.c.v. dynorphin administration may, in part, be due to behavioral activation (feeding). As well, these data indicate that both opioid as well as α 1 -adrenergic receptors within the CNS are involved in mediating the pressor, tachycardic and feeding responses of conscious rats given i.c.v. injections of dynorphin A.

Hemodynamic responses (blood pressure, as well as cardiac output (CO), peripheral and CNS blood flow changes measured via radioactive microspheres) were analyzed in anesthetized rats 2 min following intrathecal (IT) administration (10 microliters) of either 5-ion control solution or 20 nmol of dynorphin A(1-13) into the lower thoracic space (T10-T12). Mean arterial pressure (MAP) significantly increased within 2 min following IT dynorphin A(1-13) due to rise in total peripheral resistance, whereas CO significantly declined. Two minutes post-IT-dynorphin A(1-13) administration spinal cord blood flow also significantly decreased for 2 cm anterior and 1 cm posterior from the tip of the spinal catheter, which reflected a significant elevation in tissue flow resistance of spinal cord vessels in spite of the reduction of CO. As well, tissue blood flow resistance was also increased at this time in the kidneys and adrenal glands. The results indicate that within 2 min after intrathecal dynorphin A(1-13) administration an acute increase in blood flow resistance of spinal cord vessels around the tip of the spinal catheter occurs, at a time when the animal is also hypertensive. It is suggested that the associated pressor response may, in part, be caused by dynorphin A evoking localized ischemia.