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Selective elimination of mu-opioid receptor expressing neurons in the rostral ventromedial medulla (RVM) does not affect periaqueductal gray (pag) stimulation-produced analgesia
Harasawa I, Lai J, Porreca F, Fields HL, Meng ID (2003) Selective elimination of mu-opioid receptor expressing neurons in the rostral ventromedial medulla (RVM) does not affect periaqueductal gray (pag) stimulation-produced analgesia. Neuroscience 2003 Abstracts 177.5. Society for Neuroscience, New Orleans, LA.
Summary: PAG stimulation produces antinociception at spinal levels by modulating RVM neuronal activity. Microinjection of saporin conjugated with the mu-opioid receptor agonist dermorphin (DERM-SAP) into the RVM selectively eliminates MOR expressing neurons and diminishes neuropathic pain symptoms (Porreca et al., 2001). The aim of the present study was to determine whether MOR expressing neurons in the RVM are required for PAG stimulation produced analgesia (PAG/SPA). The minimum electrical current required to inhibit the tail flick response was compared in barbiturate-anesthetized rats given a single RVM injection of SAP or DERM-SAP 3-4 weeks prior to testing. Thresholds in SAP and DERM-SAP treated rats were not different. Furthermore, microinjection of the glutamate receptor antagonist kynurenic acid (10 mM, 800 nl) into the RVM disrupted PAG/SPA in both SAP and DERM-SAP treated rats. These results indicate that 1) mu-receptor expressing neurons in the RVM are not necessary for PAG/SPA, and 2) excitatory amino acid transmission in the RVM is critical for PAG/SPA. In additional experiments, inhibition of neurotransmitter release in the RVM by the microinjection of cobalt chloride (CoCl2, 100 mM, 800 nl), produced significant antinociception only in DERM-SAP treated rats. This finding suggests that DERM-SAP injections result in increased tonic inhibition of RVM neurons and that CoCl2 disinhibits these neurons to produce antinociception. Tonic inhibition of off-cells would account for our failure to find off-cells in DERM-SAP treated rats.
Related Products: Dermorphin-SAP / MOR-SAP (Cat. #IT-12)
Cholinergic activity enhances hippocampal CA1 long-term potentiation during walking in rats
Leung LS, Shen B, Ma J, Rajakumar N (2003) Cholinergic activity enhances hippocampal CA1 long-term potentiation during walking in rats. Neuroscience 2003 Abstracts 255.5. Society for Neuroscience, New Orleans, LA.
Summary: Long-term potentiation (LTP) at the basal dendrites of CA1 pyramidal cells was induced by a single 200-Hz stimulation train (0.5-1 sec duration) in freely behaving rats during one of four behavioral states – awake-immobility (IMM), walking, slow-wave sleep (SWS) and rapid-eye-movement sleep (REMS). Field excitatory postsynaptic potentials (fEPSPs) generated by basal dendritic excitation of CA1 were recorded before and up to 20 hours after the tetanus. Following a tetanus during any behavioral state, basal dendritic LTP was > 170% of the baseline for the first 30 min after the tetanus and decayed to ~125% at 20 hours after. LTP induced during walking was significantly larger than that induced during IMM, SWS or REMS. LTP induced during IMM, SWS and REMS was not significantly different from each other. To test the hypothesis that septohippocampal cholinergic activity enhanced LTP during walking than during immobility, rats were either pretreated with muscarinic cholinergic antagonist scopolamine (5 mg/kg i.p.) or given selective cholinotoxin IgG192-saporin in the medial septum. Pretreatment with scopolamine decreased the LTP induced during walking but did not affect that induced during IMM, such that the difference between LTP induced during walking and IMM was abolished. In IgG192-saporin injected rats, there was no difference in the LTP induced during walking and during IMM, and scopolamine did not reduce the LTP induced during walking. In contrast, sham-lesioned rats, like other control rats, showed larger LTP induced during walking than during IMM, and LTP induced during walking was attenuated by scopolamine. This appears to be the first demonstration of an enhancement of hippocampal LTP by physiologically activated septal cholinergic inputs. LTP of the CA3 to CA1 synapses may serve important behavioral functions.
Related Products: 192-IgG-SAP (Cat. #IT-01)
H3 receptor antagonists modulate behaviour in a visual spatial attention task in rats with selective lesions of the nucleus basalis magnocellularis
Muir JL, Harrison FE (2003) H3 receptor antagonists modulate behaviour in a visual spatial attention task in rats with selective lesions of the nucleus basalis magnocellularis. Neuroscience 2003 Abstracts 296.7. Society for Neuroscience, New Orleans, LA.
Summary: It is well known that the cholinergic system suffers a large amount of damage in Alzheimer’s Disease (AD). The histaminergic system is known to interact with the cholinergic system but is thought to be largely spared in AD. Compounds which affect histaminergic transmission therefore offer a new further therapeutic avenue to be considered. The effects of two selective H3 receptor antagonists, Thioperamide (1.0, 3.0, 10.0mg/kg) and Ciproxifan (1.5, 3.0, 5.0mg/kg), were investigated for their ability to modulate visual spatial attention using the Five Choice Serial Reaction Time Task. The animal model used was that of cholinergic lesions of the nucleus basalis Magnocellularis (nbM) in the basal forebrain using the selective immunotoxin IgG Saporin. Thioperamide, without affecting overall accuracy, showed very strong trends towards a reduction in anticipatory responses in both sham and lesion groups and also showed a slight reduction in perseverative responses. The more potent Ciproxifan showed no overall change in accuracy but led to a reduction in the anticipatory responses in nbM lesioned animals at all three doses of the drug, returning them to equivalent levels of responses to the sham group. This effect was independent of any overall decrease in activity levels as there were no concomitant changes in response latencies or number of trials completed. Hence these pharmacological manipulations reduced the levels of impulse behaviours manifest by lesioned animals.
Related Products: 192-IgG-SAP (Cat. #IT-01)
Progressive effects of cholinergic depletion on cortical functional properties in the somatosensory cortex of rats
Herron P, Ismail NS (2003) Progressive effects of cholinergic depletion on cortical functional properties in the somatosensory cortex of rats. Neuroscience 2003 Abstracts 61.11. Society for Neuroscience, New Orleans, LA.
Summary: The amount and duration of cholinergic depletion of basal forebrain input appear to be important for how significant the functional capacity of cortical neurons and behavior are affected. Firstly, it is not known whether there is a correlative relationship between the level of cholinergic depletion and the level of degraded functional properties or whether there is a threshold of depletion, beyond which no further degradation occurs. Secondly, it is not known whether similar levels of cholinergic depletion over different periods cause the similar or different effects on functional capacities and behavior. These experiments were done in the posteromedial barrel subfield (PMBSF) cortex of young adult Sprague-Dawley rats. Selective lesion of cholinergic neurons in the NBM was achieved with cortical or intraventricular injections of the immunotoxin (IT), 192 IgG saporin. Electrophysiological recordings and whisker use in exploratory behavior were monitored for different post-injection survival periods. Results show that cholinergic depletion causes a significant decrease in the magnitude of evoked activity and an increase in the size of receptive fields for different periods. Observations of exploratory behavior showed that animals used whiskers controlled by cholinergic depleted cortex less than the whiskers controlled by non-cholinergic depleted cortex. Thus, cholinergic depletion leads to effects that significantly alter the functional capacity of the cortex and the behavioral use of those whiskers.
Related Products: 192-IgG-SAP (Cat. #IT-01)
Purkinje cell depletion by ox7-saporin impairs eyeblink conditioned excitation and inhibition in rats.
Nolan BC, Freeman JH (2003) Purkinje cell depletion by ox7-saporin impairs eyeblink conditioned excitation and inhibition in rats. Neuroscience 2003 Abstracts 87.3. Society for Neuroscience, New Orleans, LA.
Summary: The role of the cerebellar cortex in conditioned excitation has been demonstrated by studies that used lesions, inactivation, and electrical stimulation (e.g., Attwell, Rahman, & Yeo, 2001, J Neurosci, 21, 5715-5722). However, very little evidence exists concerning the role of the cerebellar cortex in conditioned inhibition. Moreover, there are multiple blink control zones in the cerebellar cortex (Hesslow, 1994, J Physiol, 476, 229-244), which complicates the interpretation of studies that use localized lesions. In the current study, rats were infused with the immunotoxin OX7-saporin into the lateral ventricles to selectively destroy Purkinje cells throughout the cerebellar cortex (Angner, et.al, 2000, Neurotox, 21, 395-404). The OX7- saporin method provides advantages relative to other methods, including the ability to deplete Purkinje cells after initial training. In Experiment 1, rats were given saline or OX7-saporin prior to excitatory conditioning training, which was established using a tone conditioned stimulus (CS) paired with a periorbital shock unconditioned stimulus (US). Rats given OX7-saporin had nearly complete Purkinje cell loss and acquisition of excitatory conditioning was severely impaired. In Experiment 2, rats were first trained with excitatory conditioning procedures, followed by infusion of either saline or OX7-saporin. After a two-week post-infusion period, the rats were given reacquisition training. After reacquiring excitatory conditioning, the rats were trained using a feature-negative discrimination procedure consisting of trials with CS-US pairings and trials with a non-reinforced tone-light compound stimulus. Rats treated with OX7-saporin showed a significant impairment in reacquisition and acquisition of conditioned inhibition. The results suggest that Purkinje cells are critically involved in the acquisition of both conditioned excitation and inhibition in rats.
Related Products: OX7-SAP (Cat. #IT-02)
Spinal neurons that possess the substance P receptor (SPR) modulate descending systems that control excitability of spinal nociceptive neurons
Khasabov SG, Ghilardi JR, Mantyh PW, Simone DA (2003) Spinal neurons that possess the substance P receptor (SPR) modulate descending systems that control excitability of spinal nociceptive neurons. Neuroscience 2003 Abstracts 13.3. Society for Neuroscience, New Orleans, LA.
Summary: We have recently shown that ablation of spinal SPR-expressing spinal neurons by intrathecal application of the cytotoxin conjugate substance P-saporin (SP-SAP) prevents the development of sensitization produced by intraplantar injection of capsaicin (Khasabov et al., 2002) and reduced hyperalgesia produced by inflammation and nerve injury (Mantyh et al., 1997; Nichols et al., 1999). Since the majority of spinal SPR-expressing neurons project to the brain, it is possible that these neurons are an integral part of ascendingdescending circuitry that modulates excitability of spinal nociceptive neurons. Here we studied the contribution of ascending SPR positive neurons in the regulation of brain stem descending pathways that pass through the dorsolateral funiculus (DLF) and modulate spinal cord excitability and sensitization. Rats were given an intrathecal injection of vehicle (0.9% NaCl, 10μl) or SP-SAP (5·10-6M, 10μl) at the lumbar enlargement 30 days prior to electrophysiological recording from lumbar spinal neurons. Spontaneous activity and evoked responses of nociceptive neurons to heat (35-51.°C) and mechanical stimuli (von Frey monofilaments) were obtained before and 1 hour after ipsilateral DLF transection. In vehicle-treated animals, DLF transection produced a 183% increase spontaneous activity, a leftward shift in the temperature-response curve, and a 60% increase in the number of impulses evoked by mechanical stimuli (n=25). In contrast, neurons in the SP-SAP group did not show any changes in spontaneous or evoked activity after DLF transaction (n=29). We conclude that ascending spinal SPR-possessing neurons modulate activity of descending inhibitory systems that pass through the DLF.
Related Products: SP-SAP (Cat. #IT-07)
Ablation of a population of NK-1 expressing neurons in the dorsal horn of the spinal cord does not induce αβ sprouting into lamina II
Woods M, Whiteside G, Pearson M, Pomonis J, Turchin P, Walker K (2003) Ablation of a population of NK-1 expressing neurons in the dorsal horn of the spinal cord does not induce αβ sprouting into lamina II. Neuroscience 2003 Abstracts 64.11. Society for Neuroscience, New Orleans, LA.
Summary: Peripheral nerve injury results in hyperalgesia and allodynia. It has been proposed that sprouting of myelinated touch responsive Aβ-fibers into the innervation territory of pain sensitive C fibers in the spinal cord contributes to these abnormal behaviors. In has further been postulated that excitatory cell death of spinal cord neurons may result in “vacant synapses” that induce sprouting (Woolf et al., 1992). We have investigated whether selectively ablating a population of cells in laminae I and II, using intrathecal (i.t.) SP-saporin (SP-SAP), will induce sprouting from deeper laminae. Male Sprague-Dawley rats were either injected i.t. at the lumbar region with SP-SAP (1 μl, 5 μM) or the sciatic nerve was axotomised at the mid-thigh level. Two weeks later the sciatic nerve was injected with the retrograde tracer, cholera toxin-β subunit (CTB) (2 μl, 2%) which selectively traces Aβ-fibers. Three days post CTB the animals were perfused, the lumbar ganglia and spinal cord harvested, sectioned and stained immunohistochemically for NK-1 and CTB. As previously described axotomy resulted in considerable CTB immunostaining in laminae I, II and III compared to non-axotomised controls in which it was present only in I and III. SP-SAP i.t. resulted in a substantial reduction of NK-1 like immunostaining in the spinal cord compared to saline injected controls. CTB was not detected in lamina II of spinal cords from animals with an ablation of NK-1 expressing cells. These results suggest that the death of dorsal horn neurons does not induce sprouting of Aβ-fibers into lamina II.
Related Products: SP-SAP (Cat. #IT-07)