Priming enhances endotoxin-induced thermal hyperalgesia and mechanical allodynia in rats

Central inflammation is an integral component and contributor of the pathology of many debilitating diseases and has been shown to produce spontaneous pain and hyperalgesia. Recently, administration of lipopolysaccharide (LPS) into the lateral ventricle of rats was shown to elicit both thermal hyperalgesia and tactile allodynia [K. Walker, A. Dray, M. Perkins, Hyperalgesia in rats following intracerebroventricular administration of endotoxin: effect of bradykinin B₁ and B₂ receptor antagonist treatment, Pain 65 (1996) 211–219]. In this study, we have replicated the LPS model with some adaptations and correlated the nociceptive behaviors with an increased expression of activated macrophages in the central nervous system. We also examined the effects of priming on LPS-induced decreases in thermal nociceptive thresholds and mechanical response thresholds following either central or peripheral administration. Intracerebroventricular (i.c.v.) administration of LPS (0.2 μg/rat) did not alter either thermal (hot plate) or mechanical (von Frey filaments) thresholds compared to baseline values in the first few hours after injection. However, priming rats by pretreating with i.c.v. LPS (0.2 μg) 24 h prior to testing with i.c.v. LPS (0.2 μg) produced significant mechanical allodynia and thermal hyperalgesia. The mechanical allodynia had an onset of 80 min after injection and a duration of 5 h. A similar time course was observed for thermal hyperalgesia, although its expression was less pronounced. Immunohistochemical studies indicated an increased expression of activated macrophages in the brain parenchyma of primed rats but not in unprimed rats. Intraperitoneal (i.p., 2 mg/kg) administration of LPS had no significant effect on either thermal or mechanical thresholds in the first few hours after injection; however, priming rats via i.p. (0.2 mg/kg) or i.c.v. (0.2 μg) LPS produced a reduction in both thermal nociceptive thresholds and mechanical response thresholds in rats given a subsequent i.p. injection of LPS. This study demonstrates that priming is an effective protocol for the induction of central inflammation and increases the duration of these behaviors after i.c.v. administration.     

Effects of imipramine on behavior and brain norepinephrine metabolism in tetrabenazine treated rats: comparative study of a single administration with repeated administrations of imipramine

The effects of a single and repeated administrations of imipramine on the tetrabenazine-induced sedation in rats were studied. The 3-methoxy-4-hydroxyphenylethyleneglycol-sulfate (MHPG-SO4) level in the brain was measured. A single administration of imipramine of 20 mg/kg had no significant effect on the rats' locomotor activity and the brain MHPG-SO4. The administration of 30 mg/kg of tetrabenazine produced marked sedation and significantly increased the brain MHPG-SO4. The imipramine pretreatment reversed the tetrabenazine-induced sedation. The brain MHPG-SO4 in the rats treated with a single administration of imipramine along with tetrabenazine decreased significantly, compared with that in the rats treated with tetrabenazine only. The administration of alpha-methyl-para-tyrosine (alpha-MT) of 250 mg/kg suppressed the reversal of the tetrabenazine-induced sedation. The administration of Ro4-4602 of 50 mg/kg and L-3,4-dihydroxyphenylalanine (L-DOPA) of 100 mg/kg had no significant effect on the reversal. The repeated daily administrations of imipramine of 20 mg/kg reversed the tetrabenazine-induced sedation and produced the locomotor hyperactivity. When the rats were treated with the repeated administrations of imipramine for five days and had tetrabenazine administered on the last day, the brain MHPG-SO4 increased significantly as compared with that in the rats treated with a single administration of imipramine and tetrabenazine. There was no difference in the amount of locomotor activity between the rats administered imipramine of 20 mg/kg and tetrabenazine and those administered imipramine of 40 mg/kg and tetrabenazine. Several considerations were given to the above-mentioned results.     

Effects of Imipramine on Behavior and Brain Norepinephrine Metabolism in Tetrabenazine Treated Rats: Comparative Study of a Single Administration with Repeated Administrations of Imipramine

Abstract: The effects of a single and repeated administrations of imipramine on the tetrabenazine-induced sedation in rats were studied. The 3-methoxy-4-hydroxyphenylethyleneglycol-sulfate (MHPG-SO₄) level in the brain was measured. 1) A single administration of imipramine of 20 mg/kg had no significant effect on the rats' locomotor activity and the brain MHPG-SO₄. The administration of 30 mg/kg of tetrabenazine produced marked sedation and significantly increased the brain MHPG-SO₄. 2) The imipramine pretreatment reversed the tetrabenazine-induced sedation. The brain MHPG-SO₄ in the rats treated with a single administration of imipramine along with tetrabenazine decreased significantly, compared with that in the rats treated with tetrabenazine only. The administration of α-methyl-para-tyrosine (α-MT) of 250 mg/kg suppressed the reversal of the tetrabenazine-induced sedation. The administration of Ro4-4602 of 50 mg/kg and L-3,4-dihydroxyphenylalanine (L-DOPA) of 100 mg/kg had no significant effect on the reversal. 3) The repeated daily administrations of imipramine of 20 mg/kg reversed the tetrabenazine-induced sedation and produced the locomotor hyperactivity. When the rats were treated with the repeated administrations of imipramine for five days and had tetrabenazine administered on the last day, the brain MHPG-SO.J increased significantly as compared with that in the rats treated with a single administration of imipramine and tetrabenazine. There was no difference in the amount of locomotor activity between the rats administered imipramine of 20 mg/kg and tetrabenazine and those administered imipramine of 40 mg/kg and tetrabenazine. 4) Several considerations were given to the above-mentioned results.     

Axonal degeneration and axonal caliber alterations following combined beta,beta'-iminodipropionitrile (IDPN) and acrylamide administration

A new model of neurofilamentous axonal abnormality is described which employs combined administration of beta,beta'-iminodipropionitrile (IDPN) and acrylamide (AC). The model was developed to test the hypothesis that IDPN-induced swelling increases the vulnerability of the distal axon to a second neurotoxic chemical insult. Rats were given a single intraperitoneal (IP) injection of IDPN (1.5 g/kg) one week before receiving a single injection of AC (75 mg/kg, IP). Axonal degeneration was observed at multiple levels along the sciatic nerve at two weeks (with reference to IDPN administration), and was not progressive up to five weeks. Quantitation of degenerating fibers demonstrated that the extent of degeneration increased distally along the sciatic nerve. Single administration of either IDPN or AC did not produce degeneration. Thus, IDPN-induced neurofilamentous swellings alter the susceptibility of the axon to AC neurotoxicity. Two variations of this model were also studied. First, rats given five daily injections of AC (30 mg/kg, IP) beginning one week following IDPN administration developed accumulations of fast axonally transported materials in IDPN-induced microtubule channels. Second, rats given chronic injections of AC (30 mg/kg, IP, five days/week, for four weeks), to reduce the delivery of neurofilaments to the proximal axon, developed less prominent axonal enlargements when challenged with IDPN. Thus, axonal atrophy can mask the development of neurofilamentous axonal swellings.     

Brain glycine levels in triazolam-treated albino rats

Summary. The present study investigates the effects of acute and chronic administration of triazolam in albino rats on glycine levels in different brain areas. Three experiments were conducted. In the first, five groups of rats were acutely treated with different doses of triazolam (0.25 mg/kg−4.0 mg/kg i.p.). In the second experiment, rats were treated chronically by a single daily dose of triazolam (started by 0.25 mg/kg and increased by time to 1.0 mg/kg) for 5 weeks, simulating clinical use. In the third, rats were treated chronically three daily doses of triazolam (started by 0.25 mg/kg and increased by time to 0.5 mg/kg) for 20 days, simulating a form of drug abuse. Brain levels of glycine and plasma levels of triazolam were measured using HPLC technique. The acute triazolam administration produced an increase in glycine levels in almost all brain areas studied. The chronic administration of single daily dose of triazolam produced normal glycine levels in most of the brain areas; this indicates the development of tolerance to glycine content increasing action of triazolam. The chronic administration of three daily doses of triazolam produced a decrease in glycine levels in almost all brain regions studied, which might be a prerequisite for oncoming withdrawal syndrome. Received December 9, 1999; accepted October 6, 2000     

Estrogen blocks the cardiovascular and autonomic changes following vagal stimulation in ovariectomized rats

The current investigation examines the effect of acute and chronic estrogen administration on baroreflex sensitivity and autonomic tone following 2 h of vagal afferent stimulation in ovariectomized female rats. Female Sprague-Dawley rats were ovariectomized and supplemented daily for 7 days with either estrogen (OVX-E2; 0.5 microg/kg; s.c.) or saline (OVX-S; 0.9%; s.c.). On the 8th day the animals were anaesthetized (sodium thiobutabarbitol; 100 mg/kg) and instrumented for recording blood pressure, heart rate and efferent vagal and renal nerve activities. The baroreflex was evoked using intravenous injection of various doses of phenylephrine hydrochloride (0.025, 0.05+/-0.1 mg/kg). Electrical stimulation of vagal afferents for 2 h produces autonomic imbalance characterized by sympathoexcitation and parasympathetic withdrawal. This protocol of vagal stimulation produced a significant increase in renal nerve activity (from 20+/-6 to 140+/-20 spikes/2 s) and decreases in both vagal nerve activity (from 22+/-3 to 10+/-2 spikes/2 s) and baroreflex sensitivity (from 0.55+/-0.05 to 0.3+/-0.05) in OVX-S female rats. However. vagal stimulation had no effect on baroreflex sensitivity or autonomic nerve activities in OVX-E2 rats. Administration of a single, bolus dose of estrogen (1 x 10(-2) mg/kg) to OVX-S rats immediately prior to termination of vagal stimulation blocked the changes in autonomic nerve activities and baroreflex sensitivity previously observed. These results suggest that both chronic and acute estrogen supplementation may provide resistance to the autonomic disturbances associated with visceral afferent activation.     

Antibody directed against GD(2) produces mechanical allodynia, but not thermal hyperalgesia when administered systemically or intrathecally despite its dependence on capsaicin sensitive afferents

Anti-GD₂ antibodies have been shown to be effective for immunotherapy of neuroblastoma and other GD₂ enriched malignancies. Infusion of anti-GD₂ antibodies frequently causes spontaneous pain and allodynia for the duration of the immunotherapy and occasionally longer lasting neuropathic pain. Bolus intravenous injection of anti-GD₂ in rats initiates mechanical allodynia as measured by withdrawal threshold of the hindpaws. In this study, thermal thresholds were measured prior to and for up to 6 h following systemic anti-GD₂ administration in adult rats. In addition, both thermal and mechanical thresholds were tested following intrathecal administration of anti-GD₂ and IgG_2a. Murine anti-GD₂ elicited mechanical allodynia when administered into either the vasculature or the intrathecal space. Effective systemic doses were 1–3 mg/kg as previously shown. Intrathecally, optimal doses ranged from 0.01 to 0.1 ng; a higher dose was ineffective. Thermal hyperalgesia was not observed via either route of administration. Intrathecal pretreatment 48–72 h prior to the experiment with capsaicin at doses sufficient to cause a 50% depletion of dorsal horn CGRP, caused a total blockade of the mechanical allodynia indicating an involvement of peptidergic fine afferent fibers. It is likely that the antibody reacts with an antigen on peripheral nerve and/or myelin to initiate its effect. The lack of observed thermal hyperalgesia is surprising especially in light of the capsaicin-associated blockade, however, it is consistent with several other immune system related models of pain.     

Plasticity of some spinal dorsal horn neurons as revealed by pentobarbital-induced disinhibition

Extracellular activity was recorded from single spinal dorsal horn neurons in physiologically intact, awake, drug-free cats before and after the intravenous administration of 20 mg/kg pentobarbital (Pb). Pb produced a series of changes in response properties that reflect a significant moment-to-moment plasticity of some spinal dorsal horn neurons. Pb administration unmasked the ability of some low-threshold (LT) neurons to respond to noxious mechanical or thermal stimuli resulting in their being reclassified as wide dynamic range (WDR) neurons. Pb also appeared to unmask an afterdischarge in some neurons following noxious mechanical stimulation. In addition, some neurons appeared to be better able to signal changes in the intensity of mechanical stimulation after Pb. Neuronal receptive fields for low threshold stimulation were reduced in many instances but enlargement was also observed. The responses of some neurons to peripheral stimulation were unchanged by Pb. We hypothesize that the relatively low doses of Pb used in the study reduced tonic inhibition of some spinal dorsal neurons although the observed effects could have been produced by excitation.     

Effects of adenosine and adenosine A2A receptor agonist on motor nerve conduction velocity and nerve blood flow in experimental diabetic neuropathy

This study examined the effects of chronic administration of adenosine and CGS 21680 hydrochloride (adenosine A(2A) receptor agonist) on motor nerve conduction velocity (MNCV), nerve blood flow (NBF) and histology of sciatic nerve in animal model of diabetic neuropathy. Adenosinergic agents were administered for 2 weeks after 6 weeks of streptozotocin-induced (50 mg/kg i.p.) diabetes in male Sprague-Dawley rats. Significant reduction in sciatic MNCV and NBF were observed after 8 weeks in diabetic animals in comparison with control (non diabetic) rats. Adenosine (10 mg/kg, i.p.) significantly improved sciatic MNCV and NBF in diabetic rats. The protective effect of adenosine on MNCV and NBF was completely reversed by theophylline (50 mg/kg, i.p.), a non-selective adenosine receptor antagonist, suggesting that the adenosine effect was mediated via adenosinergic receptors. CGS 21680 (0.1 mg/kg, i.p.) significantly improved NBF; however, MNCV was not significantly improved in diabetic rats. At a dose of 1 mg/kg, neither MNCV nor NBF was improved by CGS 21680 in diabetic rats. ZM 241385 (adenosine A(2A) receptor antagonist) prevented the effect of CGS 21680 (0.1 mg/kg, i.p.). Histological changes observed in sciatic nerve were partially improved by the adenosinergic agents in diabetic rats. Results of the present study, suggest the potential of adenosinergic agents in the therapy of diabetic neuropathy.     

Antagonism of dithiobiuret toxicity in rats

Daily administration of dithiobiuret (DTB, 1 mg/kg X 6 days, ip) produced delayed onset muscle weakness in rats as indicated by failure in a treadmill test. In nerve-muscle preparations from DTB-intoxicated rats neuromuscular toxicity was manifested as contractile fatigue during tetanic nerve stimulation. As muscle weakness developed, feed intake decreased and the animals lost body weight. Water intake was not altered during this time, but urine output was increased concomitant with the development of muscle weakness and resulted in a state of negative water balance. Daily administration of d-penicillamine (d-PEN) antagonized DTB-induced treadmill failure in a dose-dependent fashion. A daily dose of d-PEN (1 mMol/kg, ip) that completely antagonized treadmill failure also antagonized the contractile fatigue, reduced feed intake, weight loss and negative water balance caused by DTB administration. In rats already intoxicated with DTB, initiating daily d-PEN treatment or discontinuing further DTB administration, caused the animals to recover normal treadmill performance after a latent period of five days. A single dose of d-PEN (1 mMol/kg, iv) was not effective in reversing treadmill failure or contractile fatigue in rats already intoxicated with DTB. Thus, continuous daily administration of d-PEN was necessary for it to be effective. A single dose of d-PEN (1 m Mol/kg, ip) administered one hr after [14C]-DTB (1 mg/kg, ip) did not affect the plasma and tissue concentrations of DTB-derived radioactivity or their corresponding elimination kinetics. Cumulative urinary and fecal excretion of DTB-derived radioactivity were also unaffected by d-PEN administration as were the relative proportions of DTB and two of its metabolites, monothiobiuret and thiuret, in urine. Other agents that produced dose-dependent antagonism of DTB toxicity were diethyldithiocarbamate, disulfiram, cysteamine and 2,2'-dipyridyl. Considering the chemical and biological properties of DTB and its antagonists, a mechanism of antagonism involving an alteration of the thiol-disulfide and/or divalent metal cation status of motor axon terminals is postulated.     

Flecainide reverses neuropathic pain and suppresses ectopic nerve discharge in rats.

We investigated effects of flecainide, a Class IC sodium channel blocker, in the rat chronic constrictive injury (CCI) and ectopic nerve discharge models. In the behavioral evaluation, 2, 6, and 12 mg/kg flecainide were intravenously given to the CCI model, and a dose-dependent analgesic effect was shown on both thermal hyperalgesia and tactile allodynia. In the electrophysiological evaluation using the ectopic nerve discharge model produced by saphenous neurectomy, i.v. administration of 2, 6, and 12 mg/kg flecainide suppressed spontaneous discharge at the peripheral nerve level in a dose-dependent fashion as with the behavioral evaluation, but flecainide did not affect nerve conduction at the dose of 12 mg/kg.     

Persistent cerebrovascular effects of MDMA and acute responses to the drug

Acutely, 3,4,-methylenedioxymethamphetamine (MDMA) induces cerebrovascular dysfunction [Quate et al., (2004)Psychopharmacol., 173, 287-295]. In the longer term the same single dose results in depletion of 5-hydroxytrptamine (5-HT) nerve terminals. In this study we examined the cerebrovascular consequences of this persistent neurodegeneration, and the acute effects of subsequent MDMA exposure, upon the relationship that normally exists between local cerebral blood flow (LCBF) and local cerebral glucose utilization (LCMRglu). Dark agouti (DA) rats were pre-treated with 15 mg/kg i.p. MDMA or saline. Three weeks later, rats from each pre-treatment group were treated with an acute dose of MDMA (15 mg/kg i.p.) or saline. Quantitative autoradiographic imaging was used to measure LCBF or LCMRglu with [(14)C]-iodoantipyrine and [(14)C]-2-deoxyglucose, respectively. Serotonergic terminal depletion was assessed using radioligand binding with [(3)H]-paroxetine and immunohistochemistry. Three weeks after MDMA pre-treatment there were significant reductions in densities of 5-HT transporter (SERT)-positive fibres (-46%) and [(3)H]-paroxetine binding (-47%). In animals pre-treated with MDMA there were widespread significant decreases in LCMRglu, but no change in LCBF indicating a persistent loss of cerebrovascular constrictor tone. In both pre-treatment groups, acute MDMA produced significant increases in LCMRglu, while LCBF was significantly decreased. In 50% of MDMA-pre-treated rats, random areas of focal hyperaemia indicated a loss of autoregulatory capacity in response to MDMA-induced hypertension. These results suggest that cerebrovascular regulatory dysfunction resulting from acute exposure to MDMA is not diminished by previous exposure, despite a significant depletion in 5-HT terminals. However, there may be a sub-population, or individual circumstances, in which this dysfunction develops into a condition that might predispose to stroke.     

Neuronal responses of the globus pallidus to systemic administration of d-amphetamine: investigation of the involvement of dopamine, norepinephrine, and serotonin

Systemic administration of d-amphetamine (d-AMP) caused significant increases in the unit activity of spontaneously firing neurons in the rat globus pallidus. Intravenous injection of 0.2 mg/kg of d-AMP produced an average increase of 32% while a cumulative dose of 6.4 mg/kg of d-AMP increased cell firing 81% above base line control. The excitatory effects of d-AMP on pallidal cells were effectively blocked and reversed by haloperidol. Increasing intravenous doses of l-amphetamine (l-AMP), totaling 12.8 mg/kg, caused a slight excitation of pallidal neurons. The average maximum increase was 18.3%. Minor rate-elevating effects were also observed after systemic administration of desmethylimipramine and clonidine. The serotonin uptake inhibitor, fluoxetine, produced varied changes in firing frequencies. Pretreatment with reserpine and alpha-methyl-p-tyrosine significantly attenuated the d-AMP-induced increase in pallidal activity. These results suggest that dopamine plays a prominent role in mediating the stimulatory effects of d-AMP on the firing rates of a population of globus pallidus cells in gallamine-paralyzed rats.     

Neuronal mechanisms responsible for ongoing activity of rabbit superior cervical ganglion neurons.

The action potentials evoked by stimulation of single preganglionic nerve fibres or of single neurons of the ganglion were recorded from postganglionic nerves of rabbit superior cervical ganglion. The averaging technique was used to improve the nerve signal-to-noise ratio. It was found by dividing the area by the area that single preganglionic nerve fibre discharges, as an average, 15 neurons of the ganglion. Action potentials were also recorded from preganglionic nerves, either appearing synchronously with the intracellular spikes recorded during ongoing activity of the ganglion neuron, or being evoked by stimulation of a single preganglionic nerve fibre. It was found by dividing the area by the area that each ongoing spike in the ganglion neuron is preceded by firing, as an average, of three preganglionic nerve fibres. Thus, 45 ganglion neurons are expected to be discharged by a preganglionic volley during their ongoing activity. This number is much lower than that found in our previous experiments (about 100 neurons). The difference suggests that in the majority of the ganglion neurons the ongoing discharges need summation of excitatory effects produced by a few converging preganglionic nerve fibres (multiple input) rather than being evoked by a single preganglionic nerve fibre (single input). Methacine, a selective muscarinic antagonist (0.3-0.5 mg/kg, i.v.), decreased by about 10% the rate of the multiple input-induced ongoing spikes while not affecting the single input-induced ongoing spikes in the ganglion neurons. This effect is probably due to the increase in the duration of after-hyperpolarization observed after the application of methacine.(ABSTRACT TRUNCATED AT 250 WORDS)     

Oral administration of dextromethorphan does not produce neuronal vacuolation in the rat brain

Dextromethorphan is a widely used antitussive agent, also showing increased recreational abuse. Dextromethorphan and its metabolite dextrorphan are non-competitive antagonists at the N-methyl-d-aspartate (NMDA) receptor ion channel. Single doses of some NMDA receptor antagonists produce neuropathologic changes in neurons of the retrosplenial/posterior cingulate cortices (RS/PC), characterized by vacuolation or neurodegeneration. To determine whether dextromethorphan produces these characteristic lesions, dextromethorphan was administered orally either as a single dose of 120mg/kg to female rats, or daily for 30 days at doses of 5-400 mg/(kg day) to male rats and 5-120mg/(kg day) to female rats. Brains were examined microscopically for evidence of neuronal vacuolation (4-6h postdose) and neurodegeneration ( approximately 24 or 48h postdose). Administration of dextromethorphan at 120mg/(kg day) in females, and at > or =150mg/(kg day) in males produced marked behavioral changes, indicative of neurologic effects. Mortality occurred at the highest doses administered. There were no detectable neuropathologic changes following single or repeated oral administration of dextromethorphan at any dose. Administration of MK-801 (9mg/kg) produced both cytoplasmic vacuolation and neuronal degeneration in neurons of the RS/PC cortex. Thus characteristic neuropathologic changes found with more potent NMDA receptor antagonists do not occur following single or repeated oral administration of dextromethorphan.     

Chronic effects of methylmercury on the cerebral function in rats

We studied the effects of the long-term and small-dose administration of methylmercury chloride (MMC) on the cerebral function in rats. MMC, at a dose of 0.7 mg/kg/day, was subcutaneously injected for 85 consecutive days in nine adult male Sprague-Dawley rats. They were then sacrificed on the final day of exposure (MMC group) after both completing observations on behavioral changes and also determining the local cerebral glucose utilization (LCGU) as an indicator of the cerebral neuronal activities. Histological examinations of the brain and the sciatic nerve were also performed. In addition, seven rats who received physiological saline also served as a control. LCGU significantly decreased in the visual cortex, lateral geniculate nucleus and medial geniculate nucleus without any accompanying histological alterations. Severe axonal degeneration of the sciatic nerve was also observed, which corresponded to the previously described crossed leg phenomenon. The present results suggest that the damage to the peripheral nerve was much more severe than that to the brain, which caused behavioral changes. Although no cerebral morphological changes were observed, brain dysfunction showed a selective involvement of the visual and auditory systems. This finding suggests that LCGU is a sensitive method for detecting the subclinical cerebral dysfunction caused by long-term and small-dose MMC intoxication in the rat brain.     

Lack of tolerance to the anxiolytic effect of diazepam and pentobarbital following chronic administration in perinatally undernourished rats

Adult female rats, undernourished at perinatal age, were evaluated for anxiolytic action in the plus-maze test after acute and chronic administration of diazepam (DZP) and pentobarbital (PTB). Deprived (D) rats chronically treated with vehicle showed an increased anxiety as compared with control (C) animals. A single intraperitoneal (i.p.) administration of DZP (1 mg/kg) or PTB (7.5 mg/kg) produced similar anticonflict effect in both C and D rats. Tolerance to the anxiolytic effect of DZP and PBT developed in C rats after a 15-day administration schedule, whereas no tolerance was observed in D animals. Drug disposition was not altered after chronic treatment either in C or in D rats. γ-aminobutyric acid (GABA)-mediated chloride uptake in microsacs of cerebral cortex of naive D rats was decreased as compared with naive C rats. After chronic DZP administration (1 mg/kg/day i.p. for 15 days), GABA-mediated ³⁶Cl⁻ influx in brain cortex microsacs of C rats did not change; however, GABA efficacy was increased in microsacs of D animals. In addition, chronic DZP treatment induced GABA-benzodiazepine uncoupling in brain cortex of C rats, but not in D animals, as assessed by chloride uptake in microsacs. Chronic PTB treatment (7.5 or 30 mg/kg/day i.p. for 15 days) did not modify GABA stimulation or GABA-PTB interaction in cortical microsacs of C or D rats.     

Effect of stimulation in the periaqueductal grey matter on activity in ascending axons of the rat spinal cord: selective inhibition of activity evoked by afferent Aδ and C fibre stimulation and failure of naloxone to reduce inhibition

In rats with prenigral decerebration, the effect was studied of electrical stimulation of the periaqueductal grey matter (PAG) on the activity recorded from axons ascending in the spinal cord. These axons were activated by electrical stimulation of afferent Aβ, Aδ and C fibres in the ipsilateral sural nerve.Stimulation of the PAG with trains of impulses by itself evoked ascending activity, but strongly depressed the impulse transmission from C fibres to neurones with ascending axons. It exerted a weaker effect on impulse transmission from Aδ fibres and had no effect on impulse transmission from Aβ fibres to neurones with ascending axons. Intravenous naloxone, 1 mg/kg, did not diminish the depressant effect of PAG stimulation.Intravenous morphine depressed the activation of ascending axons from afferent C fibres (0.5 mg/kg) more markedly than that from afferent Aδ fibres (2 mg/kg), but did not modify the depression of ascending activity produced by PAG stimulation. Naloxone antagonized the depressant effect of morphine.The results indicate that PAG stimulation inhibits ascending activity evoked by noxious stimuli by a mechanism which does not necessarily involve endogenous opiates.     

Dopaminergic modulation of sensory responses of striatal neurons: single unit studies

The extracellular single unit responses of striatal neurons to repetitive stimulation of the sciatic nerve were recorded in the urethane anesthetized rat. Changes in the magnitude of these responses after pharmacological manipulation of dopamine (DA) neurotransmission were evaluated. While the intravenous administration of 0.25 mg/kg i.v. amphetamine (AMPH) had no significant effect on baseline firing rates as compared to saline controls, the magnitudes of excitatory and inhibitory evoked single unit responses were significantly decreased by 68% by AMPH. Further, this reduction in response magnitude produced by AMPH was completely blocked by pretreatment with 0.5 mg/kg i.v. haloperidol or by intrastriatal 6-hydroxydopamine lesions. This indicates that the observed effect is mediated by dopamine located in nerve terminals within the striatum. These results suggest that DA functions to modulate the responsiveness of striatal neurons to afferent signals.     

Destruction of the sympathetic nervous system in neonatal rats and hamsters by vinblastine: prevention by concomitant administration of nerve growth factor

If the primary mechanism by which nerve growth factor (NGF) gains access to the cell body is a specific uptake and retrograde transport from the periphery, then an inhibitor of axoplasmic transport would be expected to produce cell death. Such an inhibitor was administered to neonatal and adult rats and hamsters. A single injection of vinblastine (0.25–0.5 mg/kg s.c.) to 2-day-old rats produced massive cell death in the superior cervical ganglia (SCG). The levels of tyrosine hydroxylase in the SCG were reduced 80% at doses of 0.4 mg/kg, a dose which was uniformly fatal. Doses of 0.25 mg/kg at two days of age resulted in a 50% mortality rate and the survivors showed a permanent, partial sympathectomy. The adrenal medulla and sensory neurons did not appear to be affected. Administration of a single injection of vinblastine at maximally tolerated doses did not destroy sympathetic neurons in animals 14 days of age or older. Chronic administration of vinblastine (0.5 mg/kg every other day for two weeks) to adult rats did not destroy sympathetic neurons. Similar results were obtained in hamsters.Concomitant administration of NGF appeared to completely prevent the cytotoxic effects of vinblastine assessed by both morphological and enzymatic criteria. Several explanations are discussed which might explain these results.The similarities in the effects of vinblastine, other drugs, and axonal crush on sympathetic neurons are noted. It is proposed that all drugs which destroy sympathetic neurons (guanethidine, 6-hydroxydopamine, vinblastine) as well as anti-NGF and axonal ligation destroy the neurons by depriving the cell body of NGF from the periphery.