Biomedical subjects

N T Maidment

Publications and source records attributed to N T Maidment.

At least 37 records · Page 2Linked to original sources

PubMed2000

Blockade of mu-opioid receptors reveals the hyperalgesic effect of orphanin FQ/nociceptin in the rat hot plate test.

Orphanin FQ (OFQ, also known as nociceptin) has been proposed to oppose the antinociceptive effect of endogenous opioid peptides in the brain. We sought to determine whether, conversely, the endogenous opioid peptides counteract a pronociceptive action of OFQ. In testing this hypothesis, naloxone, a non-selective opioid receptor antagonist, was used to block the action of endogenous opioid peptides. We then examined whether OFQ would produce hyperalgesia in the absence of such an endogenous opioidergic tone. Neither naloxone (1 mg kg(-1); s.c.) nor OFQ (up to 30 nmol; i.c.v.) alone induced any significant change in mean hot plate latency. However, OFQ dose-dependently produced hyperalgesia in rats pretreated with naloxone, implying that OFQ can indeed produce hyperalgesia once an endogenous opioidergic tone is inhibited. In subsequent studies, we used subtype selective opioid receptor antagonists to determine which class of opioid receptor is involved in this response. The effect of naloxone was reproduced using the selective mu-opioid receptor antagonist CTOP (D-Phe-Cyc-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2), but not by administration of the delta-opioid receptor antagonist, naltrindole (NTI) or the kappa-opioid receptor antagonist nor-binaltorphimine (nor-BNI). These results suggest that endogenous opioid peptides acting at the mu-, but not kappa- or delta-opioid receptor may be counteracting the hyperalgesic effect of OFQ in rats.

Animals↗

PubMed1999

Orphanin FQ/nociceptin blocks acquisition of morphine place preference.

Orphanin FQ/nociceptin (OFQ/N) suppresses the activity of the dopaminergic mesolimbic reward pathway yet reportedly fails to produce conditioned place aversion or preference. The present study sought to determine if this peptide could attenuate the development of morphine place preference. Male rats were administered OFQ/N (3 to 30 nmol intracerebroventricularly) during the induction of morphine (3 mg/kg subcutaneously) place preference. Animals receiving 3 or 10 nmol (but not 30 nmol) OFQ/N showed significant reductions in the development of place preference to morphine.

Analysis of Variance↗

PubMed1999

Tolerance develops to the inhibitory effect of orphanin FQ on morphine-induced antinociception in the rat.

Recent studies that intracerebroventricular (i.c.v.) administration of orphanin FQ (OFQ) blocks opioid-induced antinociception in a variety of animal models of pain. In the present study, we sought to investigate the inhibitory effect of OFQ on morphine-induced antinociception using the hot plate test in rats and to examine whether tolerance develops to the anti-opioid effect of the peptide. Microinjection of OFQ (50nmol, i.c.v.) significantly attenuated the antinociceptive effect of morphine without affecting baseline hot plate latencies, suggesting that modification of morphine-induced antinociception can be achieved via activation of the ORL-1 receptor by OFQ with no apparent mu opioid receptor blockade or interference with basal nociceptive responses. Chronic treatment with OFQ (50 nmol/day for 5 days) produced a complete loss of the inhibitory effect of the peptide indicating that tolerance developed to the anti-opioid effect of OFQ. Taken together, these results indicate that neuronal plasticity may occur following chronic use of OFQ as is evident for the other opioid agonists.

Analgesics, Opioid↗

PubMed1999

Orphanin FQ and behavioral sensitization to cocaine.

The recently identified endogenous ligand for the ORL-1 (opioid receptor-like) receptor, orphanin FQ, has been shown to induce hypolocomotion and to decrease extracellular dopamine levels in the nucleus accumbens (N.Acc) after intraventricular (ICV) administration. This study investigated the effect of intraventral tegmental area (VTA) administration of orphanin FQ on the hyperlocomotor effects of peripheral cocaine administration and on the development of behavioral sensitization to cocaine. The administration of cocaine (40 mg/kg IP) once daily for 3 days to male Sprague-Dawley rats resulted in an enhanced locomotor response to a subsequent challenge of cocaine (10 mg/kg IP) 5 days later. The bilateral administration of orphanin FQ (10 microg/side or 30 microg/side) into the VTA 5-10 min prior to the administration of cocaine (40 mg/kg IP) produced a transient (15-30 min) decrease in the hyperlocomotor response to cocaine on day 1 but not on days 2 and 3 of the sensitization paradigm. Such orphanin FQ pretreatment on days 1-3 had no effect on the development of a sensitized response to cocaine (10 mg/kg IP) 5-7 days after the last orphanin FQ injection. However, repeated intra-VTA administration of orphanin FQ (30 microg/side) alone for 3 days resulted in a sensitized response to a single dose of cocaine (10 mg/kg IP) given 5-7 days later. These results indicate that orphanin FQ decreases the activity of mesolimbic dopamine neurons via an action in the VTA, an effect that is both transient and demonstrates rapid tolerance, and consequently, is insufficient to prevent the development of cocaine sensitization. The ability of the peptide to induce cocaine sensitization when administered alone despite its acute inhibitory effects is unique and requires further study to elucidate the mechanisms responsible.

Amino Acid Sequence↗

PubMed1999

Extracellular glutamate in the dorsal horn of the lumbar spinal cord in the freely moving rat during hindlimb stepping.

The capacity to reestablish locomotor function after complete spinal cord transection in the adult mammal is now well documented. Further studies have shown different neurotransmitters to be involved in the initiation and maintenance of these locomotor patterns. However, there has been no in vivo evidence of the changes in glutamate or any other neurotransmitter in the extracellular space of the dorsal horn during an alternating motor pattern such as hindlimb stepping. This study describes an in vivo microdialysis technique to measure extracellular glutamate in the dorsal horn of the spinal cord in the fully awake intact rat. A concentric microdialysis probe was placed in the dorsal horn at L5, and 18 h later dialysate samples were collected at 20-min intervals before, during, and after 20 min of hindlimb stepping. During stepping, extracellular glutamate rose 150% above resting levels and returned to resting levels 40 min later. This increase may have occurred either as a result of primary afferent depolarization or modulation by the descending and ascending supraspinal pathways. In another series of experiments extracellular glutamate was, therefore, measured in the dorsal horn of the chronic spinally transected rat during 20 min of hindlimb stepping. Although the spinal group did not take as many steps as the intact group, those taking more than 40 steps showed a significant rise in extracellular glutamate, and the number of steps taken by the individual spinal rats correlated positively with the individual values of extracellular glutamate (r2 = 0.63). These results are consistent with glutamate being an important neurotransmitter in the spinal cord in normal locomotion.

Animals↗

PubMed1999

Gabapentin modifies extracellular opioid peptide content in amygdala: a microdialysis study.

Opioid peptide release was monitored in the amygdala and hippocampus of freely moving rats following a single oral administration of gabapentin using microdialysis. Extracellular opioid peptide levels were elevated above basal levels in the amygdala within the first 60 (54%) and 90 min (68%) after gabapentin administration. Levels returned to basal conditions 120 min following the treatment. No significant changes were detected in the hippocampus. The majority of immunoreactive material recovered from the amygdala following gabapentin administration was identified as Leu-enkephalin and Met-enkephalin by high performance liquid chromatography (HPLC) analysis. It is proposed that the enhanced opioid peptide release in the amygdala induced by gabapentin might be involved with the antiepileptic effects as well as with some adverse events produced by this drug.

Acetates↗

PubMed1999

Opioid peptide systems following a subconvulsant dose of pentylenetetrazol in rats.

The development of epilepsy and a progressive increase in susceptibility to seizures may involve changes in inhibitory and excitatory systems from the beginning of the process. The present study was focused to analyze the opioid peptide changes induced by a chemical sub-convulsant stimulation. Experiments were carried out to determine opioid peptide release, mu receptor binding and proenkephalin expression in rat brain, as well as nociceptive responses, following the administration of a sub-convulsant dose of pentylenetetrazol (PTZ) (30 mg/kg, i.p.). Membrane binding experiments revealed reduced number of mu binding sites (Bmax) in cortex and amygdala, but not in striatum and hippocampus, an effect that was evident only 24 h, but not 28 days, after PTZ treatment. In situ hybridization experiments suggested a significant enhancement of proenkephalin mRNA expression in specific brain regions 24 h after PTZ treatment. Microdialysis combined with a universal opioid peptide radioimmunoassay revealed extracellular opioid peptide levels to be elevated in the amygdala (137%) 90 min after PTZ administration. Evaluation of nociceptive responses using the Randall-Selitto test showed an analgesic effect short term (30-90 min) after PTZ injection. Collectively, these data provide evidence for a significant activation of opioid peptide systems as a consequence of the administration of a sub-convulsant dose of PTZ. These neurochemical changes may play an important role in the progression of epileptogenesis.

Animals↗

PubMed1999

Orphanin FQ/nociceptin modulation of mesolimbic dopamine transmission determined by microdialysis.

Orphanin FQ has been reported to suppress extracellular dopamine levels in the nucleus accumbens after intracerebroventricular administration. This study sought to provide evidence for an intra-ventral tegmental site of action for this effect using a dual-probe microdialysis experimental design. Orphanin FQ was applied to the ventral tegmental area of anesthetized rats by reverse dialysis while extracellular dopamine was sampled with a second dialysis probe in the nucleus accumbens. Orphanin FQ at a probe concentration of 1 mM (but not at 0.1 mM) significantly reduced nucleus accumbens dialysate dopamine levels. The receptor-inactive analogue, des-Phe1-orphanin FQ (1 mM), produced a small but significant increase in nucleus accumbens dialysate dopamine levels. Simultaneous measurement of ventral tegmental area dialysate amino acid content revealed significant increases in both GABA and glutamate during infusion of orphanin FQ (1 mM). To determine if increased GABA overflow mediates the action of orphanin FQ on mesolimbic neurons, orphanin FQ (10 nmol) was microinjected directly into the ventral tegmental area in the presence or absence of the GABA(A) receptor antagonist, bicuculline (1 nmol). Bicuculline transiently blocked the suppressive action of orphanin FQ on accumbens dialysate dopamine levels. These data indicate that orphanin FQ decreases dopamine transmission in the nucleus accumbens by inhibiting dopamine neuronal activity in the ventral tegmental area through a mechanism that may involve an increased overflow of GABA.

Amino Acids↗

PubMed1999

Cerebral microdialysis combined with single-neuron and electroencephalographic recording in neurosurgical patients. Technical note.

Monitoring physiological changes in the brain parenchyma has important applications in the care of neurosurgical patients. A technique is described for measuring extracellular neurochemicals by cerebral microdialysis with simultaneous recording of electroencephalographic (EEG) and single-unit (neuron) activity in selected targets in the human brain. Forty-two patients with medically intractable epilepsy underwent stereotactically guided implantation of a total of 423 intracranial depth electrodes to delineate potentially resectable seizure foci. The electrodes had platinum alloy contacts for EEG recordings and four to nine 40-microm microwires for recording single-unit neuron activity. Eighty-six electrodes also included microdialysis probes introduced via the electrode lumens. During monitoring on the neurosurgical ward, electrophysiological recording and cerebral microdialysis sampling were performed during seizures, cognitive tasks, and sleep-waking cycles. The technique described here could be used in developing novel approaches for evaluation and treatment in a variety of neurological conditions such as head injury, subarachnoid hemorrhage, epilepsy, and movement disorders.

Adolescent↗

PubMed1998

Repeated heroin administration increases extracellular opioid peptide-like immunoreactivity in the globus pallidus/ventral pallidum of freely moving rats.

Microdialysis was used to investigate the effects of heroin administration on extracellular opioid peptide levels in the globus pallidus/ventral pallidum of freely moving rats. Two injections of heroin (0.6 mg/ kg i.p.) were given 3 h apart. The first injection had no significant effect on opioid peptide levels, but the second injection produced a transient yet significant increase (+268%) in opioid peptide-like immunoreactivity in pallidal dialysates, peaking 1 h after injection. This effect was blocked by administration of naloxone (3 mg/kg i.p.) prior to the second injection. The implications of these data are discussed with regards to the role of the endogenous opioid peptide system in opiate reward.

Analysis of Variance↗

PubMed1998

Dopaminergic and glutamatergic interactions in the expression of self-injurious behavior.

Self-injurious behavior occurring in persons with severe mental retardation is a clinically significant and poorly understood problem. Multiple neurotransmitter systems have been implicated in the pathogenesis of this behavior, particularly dopaminergic, opioidergic, and serotonergic systems. Pemoline, a central stimulant, administered systemically at high doses reliably produces self-biting behavior in the rat. The systemic bolus of pemoline produces sustained neostriatal levels of pemoline for over 24 h in a continuous infusion paradigm. Studies of the effect of cortical lesions on pemoline-mediated behaviors reveal that cortical damage, as is common in profound mental retardation, lowers the threshold for pemoline-induced self-biting behavior. Data from the corticostriatal slice suggests that sustained exposure to pemoline produces a shift in N-methyl-D-aspartate receptor-mediated responses rendering them more susceptible to dopaminergic enhancement. Thus, dopaminergic and glutamatergic interactions appear to play an important role in the development and expression of self-biting in the pemoline model.

Animals↗

PubMed1998

Opioid regulation of pallidal enkephalin release: bimodal effects of locally administered mu and delta opioid agonists in freely moving rats.

The globus pallidus and ventral pallidum receive dense enkephalinergic innervation from the dorsal and ventral striatum, respectively. A previous study demonstrated peripheral morphine administration to increase pallidal enkephalin release. To determine whether such opioid stimulatory effects may be mediated directly in the pallidum, in vivo microdialysis was used to study the effects of local administration of several concentrations of the mu receptor agonists morphine and morphine-6-glucuronide (M6G) as well as the the delta receptor agonist SNC80 on pallidal enkephalin release in freely moving rats. Low concentrations of morphine or M6G (1-10 nM) enhanced the release of enkephalins, an effect that was reversed by coadministration of the mu receptor antagonist beta-funaltrexamine (beta-FNA). A similar stimulatory effect was observed with a low concentration of SNC80 (50 nM), an effect that was blocked by the delta antagonist naltrindole (NTD). High concentrations of morphine (100 nM to 100 microM) had little or no effect, whereas M6G (10 microM) suppressed enkephalin release, an effect that was reversed by beta-FNA. Similarly, a high concentration (5 microM) of SNC80 suppressed enkephalin release. However, this effect was not blocked by NTD but was attenuated by beta-FNA, suggesting a mu receptor-mediated action. These results offer in vivo evidence of bimodal (i.e., stimulatory and inhibitory) effects of mu and delta opioid agonists on enkephalin release in the pallidum.

Analgesics, Opioid↗

PubMed1997

Presynaptic versus postsynaptic localization of mu and delta opioid receptors in dorsal and ventral striatopallidal pathways.

Parallel studies have demonstrated that enkephalin release from nerve terminals in the pallidum (globus pallidus and ventral pallidum) can be modulated by locally applied opioid drugs. To investigate further the mechanisms underlying these opioid effects, the present study examined the presynaptic and postsynaptic localization of delta (DOR1) and mu (MOR1) opioid receptors in the dorsal and ventral striatopallidal enkephalinergic system using fluorescence immunohistochemistry combined with anterograde and retrograde neuronal tracing techniques. DOR1 immunostaining patterns revealed primarily a postsynaptic localization of the receptor in pallidal cell bodies adjacent to enkephalin- or synaptophysin-positive fiber terminals. MOR1 immunostaining in the pallidum revealed both a presynaptic localization, as evidenced by punctate staining that co-localized with enkephalin and synaptophysin, and a postsynaptic localization, as evidenced by cytoplasmic staining of cells that were adjacent to enkephalin and synaptophysin immunoreactivities. Injections of the anterograde tracer Phaseolus vulgaris leucoagglutinin (PHA-L) or the retrograde tracer Texas Red-conjugated dextran amine (TRD) into the dorsal and ventral striatum resulted in labeling of striatopallidal fibers and pallidostriatal cell bodies, respectively. DOR1 immunostaining in the pallidum co-localized only with TRD and not PHA-L, whereas pallidal MOR1 immunostaining co-localized with PHA-L and not TRD. These results suggest that pallidal enkephalin release may be modulated by mu opioid receptors located presynaptically on striatopallidal enkephalinergic neurons and by delta opioid receptors located postsynaptically on pallidostriatal feedback neurons.

Animals↗

PubMed1997

Persistence of the releasable pool of CCK in the rat nucleus accumbens and caudate-putamen following lesions of the midbrain.

Previous studies have identified populations of dopamine neurons in the midbrain that colocalize cholecystokinin some of which project to the nucleus accumbens and caudate-putamen. The contribution of dopamine-colocalized peptide to the total releasable pool of cholecystokinin in these brain regions was investigated using microdialysis. Dopamine, dihydroxyphenylacetic acid and cholecystokinin immunoreactive levels in dialysates of the posterior medial nucleus accumbens and medial caudate-putamen were determined following 6-hydroxydopamine lesions of the ventral tegmental area and substantia nigra or transection of the medial forebrain bundle. An 89-99% depletion in basal extracellular dihydroxyphenylacetic acid and an 87-99% decrease in veratridine-evoked extracellular dopamine levels was observed in the nucleus accumbens and caudate-putamen, 4 weeks after 6-hydroxydopamine lesion. No statistically significant difference was observed between lesioned and control animals in the basal or veratridine-evoked extracellular level of cholecystokinin immunoreactivity in either region. Similarly, transection of the medial forebrain bundle failed to significantly deplete the releasable pool of cholecystokinin immunoreactivity in the nucleus accumbens or caudate nucleus despite 89-99% depletions of dopamine and its metabolite. These data suggest that midbrain dopamine or non-dopaminergic cells are not the primary source of releasable cholecystokinin in the posterior medial nucleus accumbens and medial caudate-putamen measured by microdialysis.

Animals↗

PubMed1997

Basal total opioid peptide release in the striatum of rats with cholestasis from bile duct resection: a study by the use of in vivo microdialysis.

The opiate withdrawal-like reaction experienced by patients with cholestatic liver disease after the ingestion of the opiate antagonist nalmefene led to the hypothesis that increased opioidergic neurotransmission/neuromodulation in the central nervous system (CNS) contributes to the pathophysiology of cholestasis. The state of antinociception, which is stereospecifically reversed by naloxone, documented in rats with cholestasis from bile duct resection supports this hypothesis. To further study the opioid system in this animal model of cholestasis, we studied the release of endogenous opioid peptides into the extracellular fluid of the dorso-lateral striatum by the technique of in-vivo microdialysis. Total opioid peptide concentration in the dialysate was measured by a solid phase radioimmunoassay with an antibody directed against the N-terminus of the Tyr-Gly-Gly-Phe-X amino acid sequence after acetylation. Basal total opioid peptide release was significantly higher after surgery in both sham resected and bile duct resected animals. However, basal (unstimulated) total opioid peptide release in the striatum of rats was not altered by cholestasis. It is inferred that the opioidergic abnormalities of cholestasis are not associated with an appreciable increase in the release of endogenous opioids into the extracellular fluid of the striatum. Abnormal processing of specific opioid peptides in cholestasis however, cannot be excluded.

Acetylation↗

PubMed1997

Amygdala kindling modifies extracellular opioid peptide content in rat hippocampus measured by microdialysis.

Opioid peptide release in the hippocampus was shown to be increased immediately following amygdala kindling stimulation in freely moving rats using microdialysis combined with a universal opioid peptide radioimmunoassay (RIA). Extracellular opioid peptide levels were elevated (55% above basal levels) within the first 10 min after electrical stimulation-induced partial seizures in previously nonkindled animals. Fully kindled rats showed lower extracellular opioid peptide levels (40% reduction) during the interictal period [16 +/- 2.1 days (mean +/- SEM) after the last stage V seizure], in comparison with values obtained from the sham-kindled group under basal conditions. However, opioid peptide release in fully kindled rats increased above 152% of interictal levels within the first 20 min after onset of fully kindled seizures, attaining peak levels equal to that of the partial kindled group and returning to prestimulation conditions 40-60 min following the ictal events. The majority of the immunoreactive material recovered from the hippocampus within the first 20 min following partial and generalized kindled seizures coeluted with dynorphin-A (1-6), dynorphin-A (1-8), and Leu-enkephalin by HPLC/RIA analysis. It is proposed that the enhanced opioid peptide release in hippocampus induced by amygdala kindling stimulation might be associated with either enhanced excitability or seizure suppression as seizure susceptibility fluctuates. The reduced interictal opioid peptide levels may also underlie some interictal behavioral disturbances.

Amygdala↗

PubMed1996

Expression of the lacZ reporter gene in the rat basal forebrain, hippocampus, and nigrostriatal pathway using a nonreplicating herpes simplex vector.

We recently demonstrated the efficacy of a nonreplicating herpes simplex type 1 virus construct, employing the Moloney murine leukemia virus long terminal repeat promoter, in providing long-term expression of the lacZ gene in rat hippocampal neurons. We now report the utility of this construct in expressing the reporter gene in neurons of the basal forebrain and substantia nigra and examine the spread of the virus to other brain regions. Dorsal and ventrolateral hippocampal formation injection of the virus resulted in numerous beta-gal-expressing cells in the stratum pyramidale, stratum oriens, stratum lacunosum-moleculare, and stratum granulosum. Scattered cells of the medial septum/diagonal band were positively stained following direct injection into this region. More intense staining of the basal forebrain was observed following hippocampal injection as a result of retrograde transport of the virus as shown by PCR analysis of viral DNA. Hippocampal injection also resulted in positive cell staining in several other afferent projection nuclei, namely, the supramammillary bodies, dorsal and caudal linear raphe, and perirhinal/entorhinal cortex. Very few cells were labeled around injection sites in the striatum or substantia nigra. However, substantia nigra zona compacta cells were blue following striatal injection, as were pallidal neurons following nigral injection. These data demonstrate the feasibility of using this virus construct to express foreign genes such as neurotrophic factors in basal forebrain and substantia nigra neurons, taking advantage of retrograde transport of the virus to preserve local anatomy.

Animals↗

PubMed1996

Pemoline produces ipsilateral turning behavior in unilateral 6-OHDA-lesioned rats.

1. Male Sprague-Dawley rats received either a unilateral injection of 6-hydroxy-dopamine or vehicle injection into the medial forebrain bundle. 2. Two weeks post surgery, all rats received a pemoline challenge (250 mg/kg s.c.), and rotational and stereotyped behaviors were videotaped and analyzed. 3. All rats regardless of injection expressed stereotyped behaviors and hyper-locomotion after pemoline challenge. 4. High performance liquid chromatography (HPLC) with electrochemical detection was used to evaluate changes in the levels of dopamine, serotonin and their metabolites in neostriata. 5. Rats with dopamine depleting lesions exhibited ipsilateral rotational behavior, indicating that pemoline, a central stimulant, is an indirect dopamine agonist in the rat. 6. The extent of dopamine depletion and serotonin elevation in the neostriatum in lesioned animals was related to the expression and degree of rotational behavior.

Animals↗