Biomedical subjects

N Dafny

Publications and source records attributed to N Dafny.

At least 19 recordsLinked to original sources

PubMed1999

Interrelations of opioids with monoamines in descending inhibition of nociceptive transmission at the spinal level: an immunocytochemical study.

This study was designed to reexamine a previous proposal of whether the opioid-like substances (OLS) being acting mainly as an intrinsic spinal mediator in the descending inhibition of nociception of the bulbospinally projecting NE-ergic, and/or 5-HT-ergic terminals in the dorsal horn by using an immunocytochemical method. The effects of intrathecal (i.t.) phentolamine (Ph), cyproheptadine (Cyp), and naloxone (Nal), administered separately or coadministered by two of them, on the expression of Fos-like-immunoreactive (FLI) neurons were observed on both sides of the lumbar dorsal horn of rats, in which equal volumes of formalin were injected into two hindpaws and the ipsilateral dorsolateral funiculus (DLF) was transected at the thoracic level antecedently. The results showed: (1) when rats were pretreated with i.t. saline, the number of nociceptive FLI neurons was significantly lowered 44% (p<0.01) on the side of the lumbar dorsal horn with intact DLF compared to the opposite side with sectioned DLF; (2) when rats were separately pretreated with i.t. Ph, Cyp and Nal, the reduction of FLI neurons on the DLF-intact side were decreased by 27% (p<0.01), 21% (p<0.01), and 25% (p<0.01), respectively; (3) when rats were pretreated with combined i.t. Ph+Cyp, the reduction on the intact side was eliminated almost completely (4%); (4) when rats were pretreated with combined i.t. Ph+Nal, the reduction on the intact side was 21% (p<0.01); and (5) when rats were pretreated with i.t. Cyp+Nal, the reduction on the intact side was 9.1%. These results suggest that: (1) nearly all the suppressive action exerted by the DLF-descending fibers are produced by the release of either NE or 5-HT as neurotransmitters at the spinal level; (2) most of the opioid-like substances act as an intrinsic spinal mediator mainly for the descending NE-ergic, but in a lesser extent for the 5-HT-ergic terminals in the dorsal horn circuitry; and (3) some OLS-ergic interneurons may only be activated by local nociceptive input.

Adrenergic alpha-Antagonists↗

PubMed1998

Dose-related effects of MK-801 on acute and chronic methylphenidate administration.

The non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist MK-801 has been shown to modulate both the effects of stimulants, such as amphetamine and cocaine, in producing locomotion and the chronic effects of stimulants in producing sensitization. In this study, we examine the interactions between MK-801 and the stimulant methylphenidate. Three different doses of MK-801 were administered 60 min prior to methylphenidate injection (2.5 mg/kg) and the acute response to MK-801 alone and the coadministration with methylphenidate were characterized. MK-801 alone was found to produce dose-dependent locomotor activation. The 0.15 mg/kg dose of MK-801 had no effect on the response to methylphenidate, while the 0. 3 and 0.6 mg/kg doses augmented the methylphenidate response. The effect of pretreatment with MK-801 on subsequent repeated methylphenidate administration was assessed. For all three doses tested, MK-801 pretreatment blocked the progressive locomotor sensitization expected during repeated methylphenidate administration. These findings suggest that MK-801 may exert a long-lasting effect on learning and memory process that result in a blocking of the development of sensitization.

Animals↗

PubMed1998

Adenosine mediates spinal norepinephrine-produced antinociception as revealed by nociceptive discharges in parafascicular neurons in rats.

The effects of intrathecal pretreatment with aminophylline on intrathecal norepinephrine-produced or serotonin-produced suppression of noxiously evoked discharges in thalamic parafascicular neurons were investigated in 35 urethane-anesthetized rats. The results showed that: (1) both intrathecal norepinephrine (15 nmol) or serotonin (20 nmol) produced significant suppression of noxiously evoked discharges in parafascicular neurons; (2) intrathecal aminophylline (120 nmol) blocked the norepinephrine-produced suppression of noxiously evoked discharges, while the same dose of aminophylline exhibited no significant effect on the serotonin-produced suppression of these discharges in parafascicular neurons. The results suggest that spinal norepinephrine-produced, but not serotonin-produced, antinociceptive effects may be mediated by adenosine as one of successive chemical links in the spinal dorsal horn circuitry.

Adenosine↗

PubMed1998

Diurnal differences in rat's motor response to amphetamine.

The dose-response characteristics and time-course of amphetamine's effect on motor activity after a single injection given to rats at four different times of the light/dark cycle was investigated using a computerized infrared motor activity recording system. After 7 days of acclimation and 2 days of baseline activity recording, rats received a single subcutaneous injection of vehicle (saline) or 0.6, 1.25 or 10 mg/kg amphetamine at 08.00, 14.00, 20.00 or 02.00. Recording was then resumed for an additional 36 to 48 h. The locomotor indices analyzed were horizontal activity, total distance, vertical activity, stereotypic activity and number of stereotypic movements. All doses (0.6. 1.25 and 10 mg/kg) significantly elevated (P < 0.01) locomotor activity compared to baseline at all times of administration. At all injection times, the maximum increase over baseline generally occurred following the 1.25 mg/kg dose of amphetamine (P < 0.001). The effect of the lower doses (0.6 and 1.25 mg/kg) on forward locomotion remained the same throughout the light/dark cycle regardless of the large difference in baseline motor activity between the light and dark phases. However, the effects of 10 mg/kg amphetamine on general stereotypic behavior, as well as the ability to cause subsequent depression of nocturnal forward ambulation, were dependent on the time of drug administration. These results showed that the circadian rhythms of locomotor and stereotypic effects of amphetamine are different.

Amphetamine↗

PubMed1998

Locus coeruleus modulates thalamic nociceptive responses via adrenoceptors.

This study investigated the parafascicular (PF) neuronal nociceptive responses and their modulation following electrical stimulation of the locus coeruleus (LC) and intrathecal (i.t.) or intracerebroventricular (i.c.v.) administration of two alpha-adrenoceptor antagonists, the alpha2-antagonist, yohimbine, and the alpha1-antagonist, prazosin. The main results were as follows: (1) the nociceptive evoked discharges in PF neurons were suppressed by preceding stimulation of LC; (2) the suppressive effect of LC stimulation on PF neurons was replaced by a facilitatory effect following pretreatment of i.t. yohimbine in 14 units tested, while i.t. prazosin failed to alter the LC-induced suppression, even when the prazosin dose was doubled; (3) i.c.v. pretreatment with prazosin strengthened the suppressive effect of LC stimulation on PF neurons; (4) i.c.v. norepinephrine (NE) administration induced, in PF neurons, a biphasic response to noxious stimulation; an early, brief (about 10 min) inhibitory effect followed by a late, long-lasting facilitatory effect; and (5) i.c.v. pretreatment of yohimbine or prazosin prevented the inhibitory or facilitatory responses released by NE, respectively. These results provide evidence that: (1) the LC-descending projections exhibit a suppressive effect on nociceptive transmission at the spinal level through alpha2-receptors; and (2) the LC-ascending projections exhibit dual effects, facilitatory and inhibitory, at the medial thalamus (PF) level through alpha1- and alpha2-receptors, respectively.

Adrenergic alpha-Agonists↗

PubMed1998

Different GABA-receptor types are involved in the 5-HT-induced antinociception at the spinal level: a behavioral study.

The effects of intrathecally (i.t.) administered GABA(A)-receptor antagonist picrotoxin or bicuculline on the antinociception produced by i.t. serotonin (5-HT), gamma-aminobutyric acid (GABA), muscimol--the GABA(A) agonist or baclofen--the GABA(B) agonist were investigated and compared using the tail-flick assay in rats. The results showed that 1) both i.t. picrotoxin (1.5 nmol) and i.t. bicuculline (0.5 nmol) exhibited a partial and later-emerged blockade on the antinociception produced by 5-HT (120 nmol) or GABA (1.5 nmol); 2) both i.t. picrotoxin and i.t. bicuculline, with the same dosages, completely blocked the antinociception produced by muscimol (1.0 nmol), but showed no effects on that produced by baclofen (0.3 nmol). The results suggest that GABA may mediate the 5-HT-induced antinociception at the spinal level, with the GABA(B)-receptors exhibiting the effect at the early-stage and the GABA(A)-receptors at the later stage of the 5-HT-induced antinociception.

Analgesics↗

PubMed1998

Time-dependent differences in the rat's motor response to amphetamine.

The dose-related motor effects of d-amphetamine given at the beginning of the light and dark cycle of rats were investigated using a computerized activity-monitoring system that recorded five different motor behavior indices. After 7 days of acclimatization and 2 days of baseline monitoring, rats were randomized into either a no-treatment time control group (n = 12), or to receive 0 (vehicle), 0.6, 1.25, 2.5, or 10 mg/kg d-amphetamine (n = 8 each) either 1 h into the light phase (0800) or another five groups at 1 h into the dark phase (2000) of day 3. The time control group exhibited a stable baseline level of activity for the length of the experiment. All doses (0.6, 1.25, 2.5, and 10 mg/kg) significantly elevated (p < 0.01) locomotor activity compared to baseline at both times of administration, but not all motor indices followed the same pattern of response. At both injection times, the maximum increase over baseline generally occurred following the 1.25 mg/kg dose of amphetamine (p < 0.001). The duration of the drug effect also increased with each dose. The stereotypic effects produced by high doses of AMP (10 mg/kg) was different when applied at the light phase compared to the dark phase, but the amphetamine effect on locomotor behavior remained the same regardless of the difference in motor activity baseline between the activity phases.

Amphetamine↗

PubMed1998

Is interferon-alpha a neuromodulator?

Interferons were initially characterized for their ability to 'interfere' with viral replication, slow cell proliferation, and profoundly alter immunity. They are a group of hormone-like molecules synthesized and secreted by macrophages, monocytes, T lymphocytes, glia, and neurons. These cytokines have been shown to have several regulatory roles and diverse biological activities, including control of cellular and humoral immune responses, inflammation, and tumor regression. In addition, there are many reports indicating that interferon-alpha (IFN-alpha) participates in the regulation of various cellular and humoral processes such as the endocrine system modulates behavior, brain activity, temperature, glucose sensitive neurons, feeding pattern and opiate activity. Therefore, IFN-alpha can be considered as a physiological modulator, with only one of its functions being the ability to hinder viral replication intracellularly.

Animals↗

PubMed1998

ATP-sensitive K+ channels are involved in the mediation of intrathecal norepinephrine- or morphine-induced antinociception at the spinal level: a study using EMG planimetry of flexor reflex in rats.

The effects of intrathecally (IT) administered glibenclamide (Gli), an ATP-sensitive K+ (KATP) channel blocker, on the antinociception produced by IT norepinephrine (NE), serotonin (5-HT), morphine (Mor), or adenosine agonist, 5'-N-ethylcarboxamide adenosine (NECA) were investigated using integrated EMG measurement of hindlimb flexor reflex (FR) in lightly pentobarbital-anesthetized rats. The results showed that: 1) NE (3, 6, or 12 nmol) or 5-HT (60, 120, or 240 nmol) each produced a dose-dependent suppression of FR EMG, respectively; 2) pretreatment with Gli (5, 10, or 20 nmol) antagonized the NE (6 nmol)-induced antinociception in a dose-dependent manner and failed to modulate the 5-HT (120 nmol)-induced suppression of FR EMG; 3) pretreatment with Gli (5, 10, or 20 nmol) also antagonize the Mor (2 nmol)-induced suppression of FR EMG in a dose-dependent manner; 4) pretreatment with naloxone (Nal, 60, 120, or 240 nmol) also antagonize the NE (6 nmol)-induced suppression of FR EMG in a dose-dependent manner; and 5) NECA (0.5, 1.0, or 2.0 nmol) produced a dose-dependent suppression of FR EMG, while pretreatment with Gli (5, 10, or 20 nmol) failed to modulate the NECA (1.0 nmol)-induced suppression of FR EMG. The results show that (a) ATP-sensitive K+ channels are involved in the NE- and Mor-induced antinociception but not 5-HT- or NECA-induced antinociception at the spinal level; (b) endogenous opioids might act as a successor of NE and then activate KATP channels to producing the antinociception.

Adenosine Triphosphate↗

PubMed1998

Behavioral tolerance to and withdrawal from multiple fluoxetine administration.

The objective of this study was to characterize the lasting effects of fluoxetine on the locomotor behavior of rats using a computerized activity-monitoring system. Challenge dosages (8, 16, and 24 mg/kg i.p.) of fluoxetine 2 h into the dark phase resulted in dose-dependent suppression of locomotor activity for 4 h following injection. Escalating (10-30 mg/kg i.p.) semidaily fluoxetine administration for the next five days resulted in decreasing locomotor activity during the multiple-administration period relative to saline control. Circadian activity patterns at the conclusion of the regimen were unchanged in shape, but featured uniform decreases in locomotor activity at every hour which were more significant during the phase. Upon discontinuation, fluoxetine-treated rats showed a significant increase in activity during the first 4 h following the first "missed" dose which was not seen in subsequent washout. Ninety-six h after the final maintenance dose, the initial three dosages were readministered, and the locomotor activity suppression in response to the rechallenge dose of fluoxetine was significantly lessened compared to initial challenge. These findings suggest that tolerance and withdrawal were obtained.

Animals↗

PubMed1998

ATP-sensitive potassium channels mediate norepinephrine- and morphine-induced antinociception at the spinal cord level.

The effects of intrathecally (i.t.) administered glibenclamide, a blocker of adenosine triphosphate-sensitive potassium ( KATP) channels, on antinociception produced by i.t. norepinephrine, morphine, or 5'-N-ethylcarboxamide adenosine, an adenosine agonist, were investigated using tail-flick assay. The results showed that: 1) i.t. norepinephrine (1 nmol), morphine (0.5 nmol) and 5'-N-ethylcarboxamide adenosine (0.5 nmol) elicited prolongation of tail-flick latency, 2) i.t. glibenclamide given in 2 different doses (5 and 10 nmol) exhibited no effects on tail-flick latency, 3) the antinociception produced by norepinephrine (1 nmol) and morphine (0.5 nmol) was blocked by glibenclamide in a dose-dependent manner, 4) glibenclamide failed to modulate the effects of 5'-N-ethylcarboxamide adenosine on tail-flick latency. These observations suggest that KATP channels may play an important role in norepinephrine- and/or morphine-induced antinociception at the spinal level.

Adenosine Triphosphate↗

PubMed1997

Methylphenidate: diurnal effects on locomotor and stereotypic behavior in the rat.

The dose-response relationship and time course of effect on motor activity after a single dose of methylphenidate given at different times of the light/dark cycle was investigated using a computerized infrared activity analysis system. After 5 to 7 days of acclimation and 2 days of baseline activity recording, rats received a single subcutaneous injection of vehicle (saline) or of 0.6, 2.5, 10 or 40 mg/kg methylphenidate at 08:00, 14:00, 20:00, or 02:00. Recording was then resumed for an additional 36 to 48 hours. The locomotor indices analyzed were horizontal activity, total distance, vertical activity, stereotypic activity, and number of stereotypic movements. Saline and 0.6 mg/kg did not alter motor activity, but 2.5, 10 and 40 mg/kg significantly increased (P < 0.01) motor activity. The time to the maximum effect and the duration of effect increased with dose. Ten mg/kg had the most robust effect on locomotor activity, while the largest dose, 40 mg/kg, elicited a more focused stereotyped activity that limited the amount of forward ambulation. A single injection of methylphenidate had only transient effects. The locomotor stimulating effects of the lower doses were similar whether given during the light or dark phase, despite the large diurnal variations in baseline activity between the activity phases. The stereotypic effects of the highest dose of methylphenidate, however, varied between the light and dark phase, with a smaller stereotypic effect during the dark phase when compared to administration during the light phase.

Animals↗

PubMed1997

Interferon modulates glucose-sensitive neurons in the hypothalamus.

Interferon-alpha (IFN) therapy induces feeding suppression that resembles anorexia. The hypothalamic glucose-sensitive neurons engage in feeding behavior. Coronal sections of rat brains, containing both the lateral hypothalamus (LH) and the ventromedial hypothalamus (VMH), as well as single-cell recordings were used to study the interaction between IFN and glucose-sensitive neurons. IFN suppressed the majority (78%) of LH neurons, while reduction in glucose concentration elicited excitation in the majority (85%) of the same neurons. The opposite effects were observed in the VMH, where IFN excited the majority of neurons (61%), and reduction in glucose concentration exerted the opposite effects in 64% of VMH recordings. Concomitant IFN and glucose reduction exhibited only the effects elicited by IFN, regardless of whether the glucose reduction caused excitation (LH) or suppression (VMH). This observation suggests that IFN causes anorexia by modulating the LH and VMH glucose-sensitive neurons.

Animals↗

PubMed1997

Sensitization to locomotor effects of methylphenidate in the rat.

A computerized activity monitoring system was used to investigate whether repeated exposure to methylphenidate (MPD) could produce sensitization to its locomotor effects in the rat. Male Sprague-Dawley rats were housed in test cages and activity was recorded continuously for 16 days as follows: Baseline activity (Day 1-2), recording following saline injection (Day 3), MPD Challenge Doses--either 0.6, 2.5, or 10 mg/kg of MPD (Day 4); five days of a repeated dose of 2.5 mg/kg (Day 5-9), five additional recording days of no treatment (Days 10-14), and MPD Re-Challenge (Day 15). Each group was re-challenged with the same doses as on day 4. Recording was resumed for an additional post-treatment day (Day 16). All injections were at 14:00. Horizontal activity, total distance, vertical activity, stereotypic activity, and number of stereotypic movements were recorded and analyzed. An augmented response (i.e., sensitization) was observed only to the lower MPD doses of 0.6 and 2.5 mg/kg. The sensitized response was more pronounced for forward ambulation than for rearing, with a complete lack of sensitization to the stereotypic effects of MPD.

Animals↗

PubMed1997

Nutritional supplementation of nucleotides restores opioid CNS-mediated phenomena in mice.

Previous experiments have demonstrated that suppression of immune function by either cyclosporin A or by a nucleotide free (NF) diet results in attenuation of morphine withdrawal symptoms in mice suggesting that immune status impacts CNS opioid-related phenomena. The present study elaborates on these initial findings by examining the effects of repletion of the NF diet with nucleotides or their precursors on opiate withdrawal. Female Balb/c mice were divided into six groups: a control group (C) given a standard lab chow diet and five experimental groups each given one of the following diets: a nucleotide free diet (NF); the NF supplemented with 0.25% RNA (NFR 0.25); the NF supplemented with 2.5% RNA (NFR 2.5) the NF supplemented with 0.06% uracil (NFU 0.06); the NF supplemented with 0.6% uracil (NFU 0.6). The mice were made morphine dependent by subcutaneous implantation of morphine pellets. Seventy-two hours after morphine pellet implantation, withdrawal was precipitated with naloxone (2 mg/kg). The mice were then observed and two indicators of withdrawal scored: jumping and diarrhea. The NF, NFR 0.25, NFR 2.5 and NFU 0.06 groups demonstrated significantly attenuation of the withdrawal signs relative to control animals. The NFU 0.6 group, however, had withdrawal scores restored to near control levels for both jumping and diarrhea. This suggests that nucleotides, particularly uracil, may play an important role in the immune-to-brain signaling pathway.

Animals↗

PubMed1997

Locus coeruleus stimulation modulates the nociceptive response in parafascicular neurons: an analysis of descending and ascending pathways.

The nociceptive responses in parafascicular neurons (PF) were recorded and studied following electrical stimulation of locus coeruleus (LC) combined with intrathecal (IT) or intracerebroventricular (ICV) administration of phentolamine (Ph), an alpha-adrenoceptor antagonist. The results revealed the following. (1) Three different PF neuronal populations were observed according to their response pattern following noxious stimulation: nociceptive-on, nociceptive-off, and nonresponsive units. Only the nociceptive-on units were studied further. (2) The nociceptive discharges in majority of PF neurons (66/87) were inhibited by electrical stimulation of the LC. (3) The inhibitory effect of LC stimulation was prevented and even reversed by pretreatment of IT Ph (40 nmol) in 22 units, or by dorsolateral funiculi transection in 24 units tested. (4) The inhibitory effect of LC stimulation was strengthened by preadministration of ICV Ph (40 nmol) in 17 units tested. (5) ICV administration of norepinephrine (NE 30 nmol) resulted in PF neurons a biphasic response to nociceptive stimulation: an early brief inhibition and a late long-lasting facilitation. (6) Pretreatment of ICV Ph (40 nmol) prior to NE injection prevented the NE-induced biphasic response. The results suggest that stimulation of LC modulates the nociceptive response of PF neurons through both ascending and descending routes. These two diverse routes exert two different effects: a predominantly inhibitory role on the nociceptive transmission at the spinal cord level by descending NE-ergic fibers, and a facilitatory role on the responsiveness of PF to noxious inputs by ascending fibers.

Adrenergic alpha-Agonists↗

PubMed1997

Effects of intrathecal monoamine antagonists on the nociceptive c-Fos expression in a lesioned rat spinal cord.

Effects of intrathecal (i.t.) administration of monoamine antagonists on formalin-induced neuronal c-Fos expression in two sides of the lumbar dorsal horn were observed in rats with unilateral transection of the dorsolateral funiculus at T11-12 level. The results showed that: 1) pretreated with i.t. normal saline (control) and then an equal volume of formalin was injected into the two hindpaws, the number of Fos-like immunoreactive neurons were 44% lower on the side of lumbar dorsal horn with intact dorsolateral funiculus (57 +/- 3.1 vs. 103 +/- 3.8). 2) Pretreatment with i.t. phentolamine (a non-selective alpha-adrenoceptor antagonist) caused an increase of Fos-like immunoreactive neurons on the intact side so showing only a reduction rate of 23% to the lesioned side (p < .01); 3) pretreatment with i.t. cyproheptadine (a 5-HT-receptor antagonist) caused a similar reduction rate of 21% (p < .01) of Fos-like immunoreactive neurons on the intact side; and 4) combined i.t. pretreatment with phentolamine and cyproheptadine caused a reduction of Fos-like immunoreactive neurons of only 4% on the intact side, namely, the differences in the number of Fos-like immunoreactive neurons on two sides of the lumbar spinal cord owing to the unilateral dorsolateral funiculus lesion were nearly abolished by i.t. coinjection of phentolamine and cyproheptadine. The results indicate that 1) peripheral noxious inputs can provoke a spinally-descending inhibitory effect on the spinal nociceptive transmission via the dorsolateral funiculus and 2) the descending fibers in dorsolateral funiculus exert their action mainly through the release of either norepinephrine or 5-HT at the spinal level.

Adrenergic alpha-Antagonists↗

PubMed1996

Interferon modulates neuronal activity recorded from the hypothalamus, thalamus, hippocampus, amygdala and the somatosensory cortex.

Neuromodulators interact with classically defined neurotransmitters to regulate a variety of biological processes. The aim of the present study was to study whether interferon-alpha (IFN) can be considered as a neuromodulator. Single cell recordings from five CNS structures were recorded before and following three different routes of IFN administration in Sprague-Dawley rats to substantiate that IFN is a neuromodulator. IFN modulated the majority of the hypothalamic (70%), amygdala (76%), hippocampus (75%) and cortical (82%) cells whether the route of administration was within the brain or given peripherally (i.v. or i.p.). The main difference among the three routes of IFN administration on the neuronal activity of these four CNS sites was the onset of the effect. However, the thalamic neurons responded differently. IFN injection within the brain modulated activity of 43% of thalamic neurons, but only 25% and 17% of the neurons when IFN was given i.v. or i.p., respectively. IFN, in general suppressed hypothalamic neuronal activity while accelerating neuronal activity in all the other studied CNS sites. In conclusion, IFN is an endogenous peptide synthesized and released both peripherally and centrally, with the same effects on neuronal activity whether it is given systemically or locally within the brain. This suggests that IFN can be considered as a neuromodulator.

Animals↗