Biomedical subjects
Publications and source records attributed to M H Millan.
Systemic injection of pilocarpine (380 mg/kg) results in the development of motor limbic seizures in rats. Olfactory bulbectomy performed 7 days prior to pilocarpine administration has a strong protective effect against the seizures. Neuropathological changes which normally occur in this seizure model do not develop in the brains of bulbectomized animals.
Intraperitoneal injection of pilocarpine (380 mg/kg) produces motor limbic seizures in rats. Focal injection into the prepiriform cortex (PC) of an N-methyl-D-aspartate receptor antagonist, 2-amino-7-phosphonoheptanoic acid (APH), 1-10 pmol, potently protects against these seizures and their pathological consequences. Sites similarly sensitive to the protective action of APH are found along a substantial part of the anterior-posterior extension of the piriform cortex. More caudal injection sites, located at the level of lateral septum are less sensitive. The anticonvulsant action of APH along the extent of the PC is localised in the vicinity of the injection site, as shown by autoradiography following focal injection of tritiated APH.
Bilateral, radiofrequency lesions of the mediobasal arcuate hypothalamus (MBH) strongly depleted levels of immunoreactive (ir)-beta-endorphin (beta-EP) in the hypothalamus and other brain tissues: these changes reflect destruction of those beta-EP-containing perikarya which are located in the MBH. No change in plasma ir-beta-EP was seen. The ir-dynorphin (DYN) content of the hypothalamus was also depressed while that of ir-Met-enkephalin was unaffected. The fall in hypothalamic ir-beta-EP was correlated with the fall in that of ir-DYN. Lesioned rats displayed only a minor, transient reduction in rate of weight gain between days 3 and 9 postsurgery: this disappeared thereafter. Further, the lesion did not affect the pattern of weight loss and regain associated with 24 h food and water deprivation. Indeed, the total 24 h (daily) food intake (FI) and water intake (WI) of lesioned rats did not differ from that of sham animals while deprivation-induced hyperphagia and hyperdipsia was not attenuated by the lesions. Moreover, the ability of naltrexone to decrease FI and WI (during both dark and light phases of the daily cycle) was not altered by the lesions. These observations indicate that central beta-EP may not be essential for the maintenance of a normal 24 h FI and WI and that opioid antagonists do not act upon the MBH or upon central beta-EP neurones in their suppression of FI and WI. Further, they suggest that central beta-EP may not fulfil an essential role in the control of body weight in the rat. Lesioned rats did, however, reveal a shift in the diurnal rhythmicity of FI and WI reflected in a reduction in the dark:light ratios of these. An alteration in the diurnal rhythmicity of sleeping and core temperature, but not locomotor activity, was also seen. The shifts in hypothalamic ir-beta-EP and ir-DYN (but no other tissue levels of any peptide) were correlated with the magnitude of the shifts in diurnal rhythmicity of ingestive behaviour. Moreover, lesions caudal to the MBH (not affecting hypothalamic ir-beta-EP or ir-DYN) or dexamethasone treatment (which affects pituitary pools of ir-beta-EP and ir-DYN) did not modify these rhythms. Thus, in these respects, the effects are 'particular' to MBH lesions modifying hypothalamic ir-beta-EP and ir-DYN. The data suggest that the MBH may play a role in the modulation of the diurnal scheduling of ingestive behaviour in the rat.(ABSTRACT TRUNCATED AT 400 WORDS)
Motor limbic seizures occur following a systemic injection of pilocarpine (380 mg/kg) in rats. Focal injection of the selective N-methyl-D-aspartate receptor antagonist, (+/-)-2-amino-7-phosphonoheptanoic acid (2-APH, 5-20 pmol), bilaterally into the entopeduncular nucleus (EP) prior to pilocarine blocks these seizures. Muscimol (50 pmol), a potent gamma-aminobutyric acid receptor agonist, injected bilaterally into EP produces a similar protection against pilocarpine-induced seizures. Thus by blocking excitatory neurotransmission or facilitating inhibition within the EP, the severity of limbic seizures can be reduced.
N-Methyl-D-aspartate (NMDA) (10 to 20 nmol) or bicuculline (15 to 50 pmol) in 0.5 microliter was infused bilaterally into the inferior colliculus or the deep layers of superior colliculus (DLSC) in normal rats, and the response to high intensity acoustic stimulation was examined. Thirty-five percent of rats receiving NMDA infusions and 42% of animals receiving bicuculline infusions into the inferior colliculus exhibited sound-induced seizures exclusively that were behaviorally similar to audiogenic seizures displayed by genetically epilepsy-prone rats. Rats receiving microinjections into the DLSC did not display sound-specific seizures. A combined pattern of spontaneous and sound-induced seizures was seen in some rats with both drugs and loci of microinjection. These data and previous studies support a role for increased excitant amino acid action and decreased efficacy of GABA in the inferior colliculus as important mechanisms involved in genetic susceptibility to audiogenic seizures.
The present study examines the role of central beta-endorphin in the generation of stimulation-induced analgesia from the ventral midbrain periaqueductal gray of freely-moving rats. Electrical stimulation of the ventral midbrain periaqueductal gray led to an antinociception against noxious heat which gradually subsided post-stimulation over a period of about 15 min. Locomotor effects (ipsilateral rotation) were also seen which were not correlated in intensity with the analgesia and which disappeared immediately with termination of stimulation. There was no indication of any aversive effects. Application of the opioid antagonist, naloxone, 10 min pre-stimulation, strongly attenuated the antinociception without changing basal thresholds. It did not influence the locomotor changes. Bilateral, radiofrequency lesions of the mediobasal arcuate hypothalamus greatly depleted immunoreactive beta-endorphin from brain tissues without affecting its levels in plasma. Lesioned rats showed a pronounced reduction of stimulation-produced antinociception in the absence of any change in basal thresholds; the locomotor effects of stimulation were not influenced. The degree of depletion of immunoreactive-beta-endorphin significantly correlated with the degree of attenuation of antinociception. These data suggest: stimulation of the ventral midbrain periaqueductal gray leads both to an antinociception and locomotor effects in freely-moving rats: these can be clearly dissociated from each other; the antinociception (but not locomotor effects) are mediated by an endogenous opioid sensitive to blockade by naloxone; and central beta-endorphin may be the endogenous opioid mediating stimulation-produced antinociception from the ventral midbrain periaqueductal gray in the rat.
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Chronic arthritic pain was induced by intradermally inoculating rats at the tail-base with Mycobacterium butyricum, which results in swelling, inflammation, and hyperalgesia of the joints. These symptoms peak at 3 weeks after inoculation and disappear by 10 weeks. The following changes were seen at 3 weeks. Immunoreactive dynorphin (ir-Dyn) and ir-alpha-neo-endorphin (alpha-NE) manifested comparable patterns of change. Their levels were increased in the anterior, but not neurointermediate, pituitary. The thalamus showed a rise in ir-Dyn and ir-alpha-NE, but no alterations were seen in other brain regions. In each case, cervical, thoracic, and lumbosacral sections of the spinal cord showed a rise in ir-Dyn and ir-alpha-NE: This was most pronounced in the lumbosacral region, where the magnitude of these shifts correlated with the intensity of arthritic symptoms. In addition, a moderate elevation in ir-methionine-enkephalin (ME) was seen in lumbosacral spinal cord. In brain, ir was not changed. The level of ir-beta-endorphin (beta-EP) was elevated both in the plasma and the anterior, but not the neurointermediate, pituitary. In addition, the content of messenger RNA encoding the beta-EP precursor, proopiomelanocortin (POMC), was enhanced in the anterior lobe. Thus, there was a selective activation of synthesis of beta-EP in, and its secretion from, the anterior lobe. In no brain tissue did levels of ir-beta-EP change. At 10 weeks postinoculation, the above changes were no longer apparent, indicating their reversibility.(ABSTRACT TRUNCATED AT 250 WORDS)
Inoculation of rats with Mycobacterium butyricum produced an arthritis of the limbs which revealed an enhanced sensitivity to noxious mechanical pressure (hyperalgesia). Arthritic rats displayed a pronounced rise in immunoreactive dynorphin in lumbo-sacral spinal cord which correlated both with the intensity and time-course of this hyperalgesia. MR-2266, a relatively preferential antagonist at the chi-opioid receptor (at which dynorphin is considered to act) potentiated this hyperalgesia. In contrast, MR 2267 (its inactive stereo-isomer) was ineffective. Further, naloxone (a weak chi-antagonist), and ICI 154,129 (a preferential delta-antagonist) were, in each case, inactive. The data demonstrate a pronounced response of spinal dynorphin to chronic arthritic pain in the rat. In addition, they raise the possibility of a function of spinal DYN, via a chi-receptor, in the modulation of chronic arthritic pain.
Rats inoculated in the tail-base with killed Mycobacterium butyricum developed an arthritic swelling and inflammation of the limbs accompanied by a hyperalgesia to noxious pressure applied thereto. These changes were maximal at 3 weeks and had subsided by 10 weeks post-inoculation. At 3 weeks, arthritic rats manifested an elevation in levels of immunoreactive (ir)-vasopressin (VP) but not ir-oxytocin (OT) in the midbrain. In contrast, ir-OT was increased in the medulla-pons while ir-VP was unaltered therein. These changes had disappeared by 10 weeks. No other brain region displayed changes. Thus, chronic arthritis is associated with selective and reversible effects upon discrete brain pools of ir-VP and ir-OT. The data clearly demonstrate that pools of ir-VP and ir-OT can be modulated independently of each other in particular brain tissues. Whether the changes are produced by, or reflect a functional response to, the pain rather than other characteristic of the arthritis, remains to be determined.
Inoculation of rats at the tail-base with Mycobacterium led to arthritic swelling and inflammation of all four limbs. Immunoreactive (ir)-dynorphin (DYN) increased in anterior but not neurointermediate pituitary. In the brain, only thalamus showed a rise and, in spinal cord, a large elevation was seen. Ir-vasopressin (VP) was not affected in these tissues but increased in midbrain. These effects might reflect a role of DYN in the control of chronic pain. In addition, they support a differential modulation of DYN as compared to VP extrinsic to the hypothalamic-neurohypophyseal axis.
Lesions of the hypothalamic paraventricular nucleus depleted immunoreactive (ir)-vasopressin (VP) and -oxytocin (OT) from rat spinal cord but failed to modify nociceptive thresholds. Further, intrathecal introduction of VP and OT into the cord failed either to influence nociceptive thresholds or to modify the antinociceptive action of morphine. However, doses of VP as low as 20 ng caused, in contrast to OT, a hind-limb muscular flaccidity and respiratory disturbances. Rats suffering from chronic arthritis did not, finally, reveal any alterations in levels or ir-VP or ir-OT in the spinal cord. Is is concluded that spinal pools of VP and OT are derived from the paraventricular nucleus and do not play a major role in nociceptive processes in the spinal cord. A role of spinal VP in motor and, possibly autonomic control is, nevertheless, indicated.
Radiofrequency destruction of the hypothalamic arcuate nucleus, the exclusive central location of beta-endorphin (beta-EP)-synthesizing neurones, greatly depressed levels of immunoreactive (ir)-beta-EP in the hypothalamus. However, the content of ir-dynorphin (DYN) therein was also decreased, in parallel with that of ir-beta-EP. Levels of ir-Met-enkephalin (ME) were, in contrast, unaffected. In the midbrain and septum, the content of ir-beta-EP was greatly depleted; in the former but not latter tissue, levels of ir-DYN were also diminished whilst levels of ir-ME were not affected in either of these structures. Further, in the neurointermediate pituitary, the content of ir-beta-EP was depressed while that of ir-DYN was not changed, whereas, in the anterior pituitary, levels of ir-beta-EP were not altered in contrast to those of ir-DYN which were decreased. Destruction of the arcuate nucleus is not, therefore, restricted to selective effects upon central beta-EP neurones: this finding is of importance for studies of the role of central beta-EP via lesioning techniques. The data suggest an interaction of the arcuate nucleus and, possibly, beta-EP with particular brain and pituitary pools of DYN.
The present study examines the influences of selective destruction of the locus coeruleus (LC) or of the ventral noradrenergic bundle (VB) upon discrete CNS and pituitary pools of vasopressin, dynorphin and related opioid peptides in the rat. The selectivity of the lesions was indicated by the fact that destruction of the LC strongly depressed levels of noradrenaline in the cortex in contrast to the hypothalamus, whereas destruction of the VB decreased noradrenaline in hypothalamus but not cortex. Rats sustaining VB lesions displayed a parallel depletion in neurointermediate, but not anterior, lobe levels of immunoreactive-(ir-dynorphin (DYN), ir-DYN, ir-alpha-neo-endorphin (ir-alpha-NE) and ir-vasopressin (ir-VP) whereas those of ir-Met-enkephalin (ir-ME) were unaffected. In the hypothalamus, the content of ir-DYN and ir-VP tended to rise and that of ir-DYN and ir-alpha-NE was significantly elevated, whereas that of ir-ME was not altered. LC destruction failed, in contrast, to modify levels of ir-VP, ir-DYN, ir-DYN, ir-alpha-NE or ir-ME in any of the above structures. It was found to, however, result in a depression in levels of ir-DYN and ir-alpha-NE, but not of ir-ME or ir-VP, in both the hippocampus and striatum whereas VB lesions were, in this respect, ineffective. Further, in the spinal cord, LC lesions resulted in a significant elevation in levels of ir-DYN and ir-alpha-NE in comparison to those of ir-DYN, ir-VP and ir-ME. Neither type of lesion significantly altered the content of any opioid peptide examined in thalamus, cortex, septum or midbrain. These data indicate that: the LC as compared to the VB interact differently with discrete pools of ir-DYN, ir-DYN, ir-alpha-NE and ir-VP in brain, pituitary and spinal cord; it is the VB rather than the LC which modulates the activity of magnocellular neurones projecting to the neural lobe of the pituitary; ir-DYN, ir-DYN and ir-alpha-NE are, in all tissues, regulated independently of ir-ME; levels of ir-DYN, ir-DYN and ir-alpha-NE are co-regulated with those of ir-VP in the hypothalamus-neural lobe axis but not in extrahypothalamic brain tissues nor the spinal cord; and DYN, DYN and alpha-NE might, in certain cases, be modulated differentially of one another, possibly reflecting alterations in precursor processing.
Selective, bilateral, radiofrequency destruction of the ventral noradrenergic bundle resulted in a substantial fall in hypothalamic but not cortical levels of noradrenaline. Ventral bundle-lesioned rats displayed, as compared to sham-operated animals, a pronounced enhancement of ambulation in both peripheral and central squares together with a reduction in immobility and an enhancement of rearing upon introduction into a novel open-field space. Grooming behaviour was not, in contrast, significantly modified. Pretreatment with the dopamine receptor antagonist, pimozide, strongly decreased this hyperactivity without significantly altering the behaviour of sham animals. These data suggest that the ventral bundle plays a role in the control of open-field locomotor behaviour and that this action may be exerted via an interaction with a dopaminergic network.
Immunoreactive-vasopressin, -oxytocin, -dynorphin, -dynorphin-(1-8), -alpha-neo-endorphin and -[Met]enkephalin were, in each case, present in greater concentrations in dorsal as compared to ventral, and lumbo-sacral as compared to cervico-thoracic, spinal cord. These differences were significantly more pronounced for vasopressin and oxytocin than for the other peptides. Lesions of the hypothalamic paraventricular nucleus depleted levels of immunoreactive-vasopressin and -oxytocin throughout the cord whereas levels of the opioid peptides therein were unaffected. In contrast, destruction of either the supraoptic or suprachiasmatic nucleus failed to change the content of immunoreactive-vasopressin, -oxytocin or any of the opioid peptides in the cord. Dehydration for 3 days depressed levels of immunoreactive-vasopressin, -oxytocin and -dynorphin in the neurointermediate lobe of the pituitary. In distinction, the levels of these were not modified in the spinal cord. Further, treatment with the synthetic corticosteroid, dexamethasone, elevated levels of immunoreactive-vasopressin, -oxytocin and -dynorphin in the neurointermediate pituitary whereas these were unaffected in the spinal cord. It is concluded that vasopressin and oxytocin in the spinal cord are predominantly derived from the paraventricular nucleus, localized in dorsal lumbo-sacral regions of the cord and insensitive to endocrinological manipulations. These pools may, thus, be modulated differently from their counterparts in the neurohypophysis and have a differing role, possibly in the control of the primary processing, autonomic or motor junctions. Further, there is no evidence from these or our prior studies for a close interrelationship of spinal cord vasopressin with dynorphin-related peptides (or oxytocin with [Met]enkephalin), likewise in contrast to the neurohypophysis.(ABSTRACT TRUNCATED AT 250 WORDS)
The present study examines the relationship of the hypothalamic paraventricular nucleus (PVN) to discrete brain and pituitary pools of immunoreactive (ir) vasopressin (VP), oxytocin (OT) and particular opioid peptides in the rat. Selective, bilateral destruction of the PVN resulted in a parallel depression in levels of ir-VP, ir-OT, ir-dynorphin (DYN), ir-DYN and ir-alpha-neo-endorphin (alpha-NE) in the neurointermediate lobe of the pituitary, whereas in its anterior counter-part no decrease in the content of any of these peptides was seen. In contrast, the content of ir-beta-endorphin (beta-EP) in the neurointermediate lobe was not significantly altered. Further, a rise in levels of ir-beta-EP in the anterior lobe, together with a fall in these in systemic plasma, was found. In the hypothalamus, in distinction to ir-met-enkephalin (ME), a diminution in the content of ir-VP, ir-OT, ir-DYN, ir-DYN, ir-alpha-NE and, in addition, ir-beta-EP was observed. In the septum, midbrain and medulla/pons, however, a selective depression in levels of ir-VP (and, as measured in the medulla/pons, of ir-OT) was seen: the content of ir-DYN, ir-DYN, ir-alpha-NE, ir-beta-EP and ir-ME was unchanged in these tissues. These data indicate that: (1) the PVN is an important contributor to neurointermediate lobe, but not anterior lobe, pools of ir-VP, ir-OT, ir-DYN, ir-DYN and ir-alpha-NE in contrast to ir-beta-EP.(ABSTRACT TRUNCATED AT 250 WORDS)
Discrete, bilateral, radiofrequency destruction of the ventral noradrenergic bundle (VB) resulted in a pronounced fall in levels of noradrenaline in the hypothalamus but not in the cortex. On days 4 and 12, but not 28, post-surgery, VB-lesioned rats were hyperactive (rearing and ambulation) upon exposure to a novel open-field space. This hyperactivity was greatly attenuated by naloxone, which did not significantly modify sham activity. These data suggest that the VB may be involved in the control of locomotor-exploratory activity via an interaction with an endorphinergic system. On day 4, but not 12 or 25, VB-lesioned rats displayed a significant elevation in core temperature (Tc). No difference in the hyperthermia elicited by introduction into the open-field was, however, seen between VB-lesioned and sham rats on day 4. In both groups, this rise in Tc was strongly attenuated by naloxone. These data indicate that the VB may be involved in the control of Tc but that it does not mediate novelty-stress evoked hyperthermia, for which endorphins are primarily responsible. Within 7 days post-surgery, VB-lesioned rats developed an enhancement of daily food intake which led to a slight obesity. From day 15 onward, a hyperdipsia was also seen in VB-lesioned rats. Naltrexone reduced the food and water intake of both sham and VB-lesioned animals but failed to totally block this hyperphagia. It is suggested that the VB is involved in the regulation of daily ingestive behaviour and that endorphins do not exclusively mediate the VB-lesion induced hyperphagia.