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Biomedical subjects

M Zhuo

Publications and source records attributed to M Zhuo.

At least 55 records · Page 3Linked to original sources
PubMed1997

Biphasic modulation of spinal nociceptive transmission from the medullary raphe nuclei in the rat.

The modulatory effects of electrical and chemical (glutamate) stimulation in the rostral ventromedial medulla (RVM) on spinal nociceptive transmission and a spinal nociceptive reflex were studied in rats. Electrical stimulation at a total 86 sites in the RVM in the medial raphe nuclei (n = 54) and adjacent gigantocellular areas (n = 32) produced biphasic (facilitatory and inhibitory, n = 43) or only inhibitory (n = 43) modulation of the tail-flick (TF) reflex. At these 43 biphasic sites in the RVM, facilitation of the TF reflex was produced at low intensities of stimulation (5-25 microA) and inhibition was produced at greater intensities of stimulation (50-200 microA). At 43 sites in the RVM, electrical stimulation only produced intensity-dependent inhibition of the TF reflex. Activation of cell bodies in the RVM by glutamate microinjection reproduced the biphasic modulatory effects of electrical stimulation. At biphasic sites previously characterized by electrical stimulation, glutamate at a low concentration (5 nmol) produced facilitation of the TF reflex; a greater concentration (50 nmol) only inhibited the TF reflex. In electrophysiological experiments, electrical stimulation at 62 sites in the RVM produced biphasic (n = 26), only inhibitory (n = 26), or only facilitatory (n = 10) modulation of responses of lumbar spinal dorsal horn neurons to noxious cutaneous thermal (50 degrees C) or mechanical (75.9 g) stimulation. Facilitatory effects were produced at lesser intensities of stimulation and inhibitory effects were produced at greater intensities of stimulation. The apparent latencies to stimulation-produced facilitation and inhibition, determined with the use of a cumulative sum method and bin-by-bin analysis of spinal neuron responses to noxious thermal stimulation of the skin, were 231 and 90 ms, respectively. The spinal pathways conveying descending facilitatory and inhibitory influences were found to be different. Descending facilitatory influences on the TF reflex were conveyed in ventral/ventrolateral funiculi, whereas inhibitory influences were conveyed in dorsolateral funiculi. The results indicate that descending inhibitory and facilitatory influences can be simultaneously engaged throughout the RVM, including nucleus raphe magnus, and that such influences are conveyed in different spinal funiculi.

Animals↗
PubMed1996

Mice lacking the gene encoding tissue-type plasminogen activator show a selective interference with late-phase long-term potentiation in both Schaffer collateral and mossy fiber pathways.

The gene encoding tissue-type plasminogen activator (t-PA) is an immediate response gene, downstream from CREB-1 and other constitutively expressed transcription factors, which is induced in the hippocampus during the late phase of long-term potentiation (L-LTP). Mice in which the t-PA gene has been ablated (t-PA-/-) showed no gross anatomical, electrophysiological, sensory, or motor abnormalities but manifest a selective reduction in L-LTP in hippocampal slices in both the Schaffer collateral-CA1 and mossy fiber-CA3 pathways. t-PA-/- mice also exhibit reduced potentiation by cAMP analogs and D1/D5 agonists. By contrast, hippocampal-dependent learning and memory were not affected in these mice, whereas performance was impaired on two-way active avoidance, a striatum-dependent task. These results provide genetic evidence that t-PA is a downstream effector gene important for L-LTP and show that modest impairment of L-LTP in CA1 and CA3 does not result in hippocampus-dependent behavioral phenotypes.

Animals↗
PubMed1996

Impaired hippocampal plasticity in mice lacking the Cbeta1 catalytic subunit of cAMP-dependent protein kinase.

Neural pathways within the hippocampus undergo use-dependent changes in synaptic efficacy, and these changes are mediated by a number of signaling mechanisms, including cAMP-dependent protein kinase (PKA). The PKA holoenzyme is composed of regulatory and catalytic (C) subunits, both of which exist as multiple isoforms. There are two C subunit genes in mice, Calpha and Cbeta, and the Cbeta gene gives rise to several splice variants that are specifically expressed in discrete regions of the brain. We have used homologous recombination in embryonic stem cells to introduce an inactivating mutation into the mouse Cbeta gene, specifically targeting the Cbeta1-subunit isoform. Homozygous mutants showed normal viability and no obvious pathological defects, despite a complete lack of Cbeta1. The mice were analyzed in electrophysiological paradigms to test the role of this isoform in long-term modulation of synaptic transmission in the Schaffer collateral-CA1 pathway of the hippocampus. A high-frequency stimulus produced potentiation in both wild-type and Cbeta1-/- mice, but the mutants were unable to maintain the potentiated response, resulting in a late phase of long-term potentiation that was only 30% of controls. Paired pulse facilitation was unaffected in the mutant mice. Low-frequency stimulation produced long-term depression and depotentiation in wild-type mice but failed to produce lasting synaptic depression in the Cbeta1 -/- mutants. These data provide direct genetic evidence that PKA, and more specifically the Cbeta1 isoform, is required for long-term depression and depotentiation, as well as the late phase of long-term potentiation in the Schaffer collateral-CA1 pathway.

Animals↗
PubMed1995

Hippocampal long-term depression and depotentiation are defective in mice carrying a targeted disruption of the gene encoding the RI beta subunit of cAMP-dependent protein kinase.

The cAMP-dependent protein kinase (PKA) has been shown to play an important role in long-term potentiation (LTP) in the hippocampus, but little is known about the function of PKA in long-term depression (LTD). We have combined pharmacologic and genetic approaches to demonstrate that PKA activity is required for both homosynaptic LTD and depotentiation and that a specific neuronal isoform of type I regulatory subunit (RI beta) is essential. Mice carrying a null mutation in the gene encoding RI beta were established by use of gene targeting in embryonic stem cells. Hippocampal slices from mutant mice show a severe deficit in LTD and depotentiation at the Schaffer collateral-CA1 synapse. This defect is also evident at the lateral perforant path-dentate granule cell synapse in RI beta mutant mice. Despite a compensatory increase in the related RI alpha protein and a lack of detectable changes in total PKA activity, the hippocampal function in these mice is not rescued, suggesting a unique role for RI beta. Since the late phase of CA1 LTP also requires PKA but is normal in RI beta mutant mice, our data further suggest that different forms of synaptic plasticity are likely to employ different combinations of regulatory and catalytic subunits.

Animals↗
PubMed1994

Effects of neonatal capsaicin treatment on descending modulation of spinal nociception from the rostral, medial medulla in adult rat.

Stimulation-produced modulation from the rostral, medial medulla (RMM) on the spinal nociceptive tail-flick (TF) reflex and on lumbar spinal dorsal horn neuron responses to noxious cutaneous stimuli was studied in adult rats treated as neonates with capsaicin or vehicle. In vehicle-treated rats (n = 7), both descending facilitatory and inhibitory influences on the TF reflex were produced from the RMM. At 11/23 sites in the RMM, electrical stimulation produced biphasic modulatory effects. Electrical stimulation facilitated the spinal nociceptive TF reflex at low intensities (5-25 microA) and inhibited the TF reflex at greater intensities (50-200 microA). The mean threshold intensity of stimulation to inhibit the TF reflex (cut-off time = 7.0 s) was 66 microA (n = 11). At 11 of 23 sites, electrical stimulation only inhibited the TF reflex; the mean threshold intensity of stimulation to inhibit the TF reflex was 50 microA (n = 11). At one stimulation site, electrical stimulation only facilitated the TF reflex at the intensities tested (5-100 microA). In capsaicin-treated rats (n = 6), the proportion of sites from which electrical stimulation only inhibited the TF reflex was significantly less (3/27 sites = 11%) than in vehicle-treated rats (11/23 = 48%). The threshold intensity of stimulation to inhibit the TF reflex from these three sites was 50 microA. The number of sites in RMM from which electrical stimulation only facilitated the TF reflex was significantly greater in capsaicin-treated rats (15/27 = 56%) than in vehicle-treated rats (1/23 = 4%). Neither the number of sites in RMM from which electrical stimulation produced biphasic modulatory effects on the TF reflex (48% and 33%, respectively) nor the intensities of stimulation or magnitudes of facilitation or inhibition of the TF reflex significantly differed between vehicle- and capsaicin-treated rats. In electrophysiological experiments, all units studied responded to non-noxious and noxious intensities of mechanical stimulation applied to the glabrous skin of the plantar surface of the ipsilateral hind foot and also to noxious heating of the skin (50 degrees C). The number of sites where electrical stimulation produced only facilitatory effects on responses of spinal dorsal horn neurons to noxious stimulation (thermal or mechanical) of the skin was significantly increased from 13% of the total sites in vehicle-treated rats to 40% in capsaicin-treated rats.(ABSTRACT TRUNCATED AT 400 WORDS)

Aging↗
PubMed1994

Nitric oxide and cGMP can produce either synaptic depression or potentiation depending on the frequency of presynaptic stimulation in the hippocampus.

Nitric oxide (NO) has been suggested to play the role of retrograde messenger during long-term potentiation (LTP) in hippocampus. In support of this idea, NO induces LTP when paired with a weak tetanus (50 Hz). An additional criterion that has been proposed for NO being a retrograde messenger is that it should also elicit long-lasting enhancement when paired with low-frequency stimulation of the presynaptic fibers. In the present study, we have tested this prediction. We find that NO produces long-lasting depression rather than potentiation when paired with low-frequency stimulation (0.25 Hz). A similar long-lasting depression is produced by 8-Br-cGMP, a cGMP analog, suggesting that NO may produce its effect by activating soluble guanylyl cyclase. These results demonstrate that NO and cGMP modulate synaptic transmission in the hippocampus by frequency-dependent mechanisms, and suggest that NO is most suitable as a retrograde messenger for LTP when the presynaptic neuron fires at high frequencies. By contrast, carbon monoxide (CO) elicits long lasting enhancement at both low and high frequencies.

Animals↗
PubMed1994

Role of guanylyl cyclase and cGMP-dependent protein kinase in long-term potentiation.

Several lines of evidence suggest that cyclic GMP might be involved in long-term potentiation (LTP) in the hippocampus. Arachidonic acid, nitric oxide and carbon monoxide, three molecules that have been proposed to act as retrograde messengers in LTP, all activate soluble guanylyl cyclase. We report here that an inhibitor of guanylyl cyclase blocks the induction of LTP in the CA1 region of hippocampal slices. Conversely, cGMP analogues produce long-lasting enhancement of the excitatory postsynaptic potential if they are applied at the same time as weak tetanic stimulation of the presynaptic fibres. The enhancement is spatially restricted, is not blocked by valeric acid (APV), nifedipine, or picrotoxin, and partially occludes LTP. This synaptic enhancement may be mediated by the cGMP-dependent protein kinase (PKG). Inhibitors of PKG block the induction of LTP, and activators of PKG produce activity-dependent long-lasting enhancement. These results suggest that guanylyl cyclase and PKG contribute to LTP, possibly as activity-dependent presynaptic effectors of retrograde messengers.

Action Potentials↗
PubMed1994

Nitric oxide and carbon monoxide as possible retrograde messengers in hippocampal long-term potentiation.

We have been investigating the hypothesis that the membrane-permeant molecules nitric oxide (NO) and carbon monoxide (CO) may act as retrograde messengers during long-term potentiation (LTP). Inhibitors of either NO synthase or heme oxygenase, the enzyme that produces CO, blocked induction of LTP in the CA1 region of hippocampal slices. Brief application of either NO or CO to slices produced a rapid and long-lasting increase in the size of synaptic potentials if, and only if, the application occurred at the same time as weak tetanic stimulation of the presynaptic fibers. The long-term enhancement by NO or CO was spatially restricted to synapses from active presynaptic fibers and appeared to involve mechanisms utilized by LTP, occluding the subsequent induction of LTP by strong tetanic stimulation. The enhancement by NO or CO was not blocked by the NMDA receptor blocker APV, suggesting that NO and CO act downstream from the NMDA receptor. In other systems, both NO and CO produce many of their effects by activation of soluble guanylyl cyclase and cGMP-dependent protein kinase. An inhibitor of soluble guanylyl cyclase blocked the induction of normal LTP. Conversely, the membrane-permeable analog 8-Br-cGMP produced a rapid onset and long-lasting synaptic enhancement if, and only if, it was applied at the same time as weak presynaptic stimulation. Similarly, two inhibitors of cGMP-dependent protein kinase blocked the induction of normal LTP, and a selective activator of cGMP-dependent protein kinase produced activity-dependent long-lasting synaptic enhancement. 8-Br-cGMP also produced an activity-dependent, long-lasting increase in the amplitude of evoked synaptic currents between pairs of hippocampal neurons in dissociated cell culture. In addition, 8-Br-cGMP, like NO, produced a long-lasting increase in the frequency of spontaneous miniature synaptic currents. These results are consistent with the hypothesis that NO and CO, either alone or in combination, serve as retrograde messengers that produce activity-dependent presynaptic enhancement, perhaps by stimulating soluble guanylyl cyclase and cGMP-dependent protein kinase, during LTP in hippocampus.

Animals↗
PubMed1993

Nitric oxide and carbon monoxide produce activity-dependent long-term synaptic enhancement in hippocampus.

Nitric oxide (NO) and carbon monoxide (CO) may act as retrograde messages for long-term potentiation (LTP) in the hippocampus. Zinc protoporphyrin IX, an inhibitor of the enzyme that produces CO, blocked induction of LTP in the CA1 region of hippocampal slices. Application of either NO or CO to slices produced a rapid and long-lasting increase in the size of evoked synaptic potentials if, and only if, the application occurred at the same time as weak tetanic stimulation. This long-term enhancement was spatially restricted to synapses from active presynaptic fibers and appeared to involve mechanisms utilized by LTP, occluding the subsequent induction of LTP by strong tetanic stimulation. The enhancement by NO and CO was not blocked by an N-methyl-D-aspartate (NMDA) receptor blocker, suggesting that NO and CO act downstream from the NMDA receptor. Also, CO produced long-term enhancement when paired with low-frequency stimulation. These results are consistent with the hypothesis that NO and CO, either alone or in combination, serve as retrograde messages that produce activity-dependent presynaptic enhancement during LTP.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed1993

Endogenous nitric oxide is required for tonic cholinergic inhibition of spinal mechanical transmission.

Recent studies have suggested that a spinal cholinergic system is important in spinal nociceptive modulation. In the present study, the role of a nitric oxide (NO)-generating system in spinal cholinergic modulation of nociception was examined in awake rats. Intrathecal (i.t.) administration of the cholinergic muscarinic receptor antagonist atropine produced a dose-dependent (1.4-14.4 nmol) decrease in the mechanical threshold for tail withdrawal, which was reversed rapidly (2-3 min) by subsequent i.t. administration of the NO precursor, L-arginine (10 pmol to 10 nmol). Intrathecal administration of L-arginine alone (10 pmol to 10 nmol) produced a dose-dependent increase in the mechanical nociceptive withdrawal threshold of the tail. The reflexive withdrawal of the tail produced by noxious heat was not significantly affected by i.t. administration of either atropine or L-arginine. Inhibition of the NO-cGMP pathway by i.t. administration of either Nw-nitro-L-arginine methyl ester (L-NAME, 10 nmol) or methylene blue (10 nmol) significantly enhanced the magnitude and prolonged the time course of the decrease in the mechanical threshold for tail withdrawal produced by i.t. pretreatment with atropine (1.4 nmol). Neither L-NAME nor methylene blue affected mechanical withdrawal thresholds in rats pretreated with saline. These data suggest that the production of endogenous NO is required for tonic inhibition of spinal nociceptive mechanical transmission. Moreover, the present data support the speculation that there exists in the lumbar spinal cord a tonic, cholinergic modulation of NO synthase.

Acetylcholine↗
PubMed1993

Vagal afferent stimulation-produced effects on nociception in capsaicin-treated rats.

1. The effects of electrical stimulation of cervical vagal afferent fibers on the nociceptive tail-flick (TF) reflex and responses of spinal dorsal horn neurons to noxious cutaneous stimulation were studied in adult rats treated as neonates with either capsaicin or vehicle. 2. Vagal afferent stimulation (VAS) produced biphasic, intensity-dependent effects on the TF reflex in vehicle-treated and untreated control rats. The TF reflex was facilitated in both groups of rats at lesser intensities of VAS (2.5-50 microA) and fully inhibited at greater intensities of VAS (50-100 microA). In contrast, biphasic effects of VAS on the TF reflex generally were not produced in rats treated as neonates with capsaicin. Facilitation of the TF reflex was produced in these rats by lesser intensities of VAS as well as by typically "inhibitory" intensities of VAS; the TF reflex was never inhibited in 6/12 rats, even at the greatest intensity of VAS tested (1,000 microA). When the TF reflex was inhibited by VAS in capsaicin-treated rats, the intensities required were significantly greater than those required in vehicle-treated or untreated rats. 3. In electrophysiological experiments, 77 neurons were recorded in the lumbar spinal dorsal horn of pentobarbital sodium-anesthetized, paralyzed rats treated as neonates with either vehicle or capsaicin. The neurons had receptive fields on the glabrous skin of the plantar surface of the ipsilateral hind foot, and all responded to mechanical stimuli of both nonnoxious and noxious intensities; 16/77 neurons also responded to noxious thermal stimulation. In vehicle-treated rats, nociceptive responses of 50% of 30 units studied were biphasically modulated by VAS, 33% were only inhibited, and 17% were only facilitated by VAS at the intensities tested (5-500 microA). In capsaicin-treated rats, nociceptive responses of 32% of 47 units studied were biphasically modulated by VAS, 15% were only inhibited, and 34% were only facilitated by VAS at the intensities tested (5-500 microA). In addition, nociceptive responses of neurons facilitated at lesser intensities of VAS and not affected at greater intensities of VAS were observed in capsaicin-treated rats (19% of the 47-unit sample). Overall, the proportion of the neuronal sample inhibited by VAS was less, and the proportion of the sample facilitated by VAS was greater in capsaicin-treated rats compared with vehicle-treated rats. 4. The efficacy of the capsaicin treatment was evaluated immunocytochemically.(ABSTRACT TRUNCATED AT 400 WORDS)

Afferent Pathways↗
PubMed1992

Inhibition of a cutaneous nociceptive reflex by a noxious visceral stimulus is mediated by spinal cholinergic and descending serotonergic systems in the rat.

The present study examined the spinal pathway and receptors that mediate nocigenic inhibition of the tail-flick (TF) reflex produced by conditioning colorectal distension (CRD). Conditioning CRD (80 mmHg; 30 s) inhibited the TF reflex in all rats studied (n = 29). In 19 rats where intensity-dependent effects of CRD were studied, conditioning CRD in 7 rats facilitated the TF reflex at lesser, non-noxious intensities (mean 7.9 +/- 2.1 mmHg) and inhibited the TF reflex at greater, noxious intensities (40-100 mmHg); conditioning CRD at all intensities tested only inhibited the TF reflex in the other 12 rats. Inhibition of the TF reflex produced by 30 s CRD was short-lasting, repeatable and graded with the intensity of CRD. The mean threshold of CRD for inhibition of the TF reflex to cut off (10 s) was 61.4 +/- 3.3 mmHg (n = 29). Intrathecal pretreatment with atropine or methysergide significantly attenuated the inhibitory effect of CRD on the TF reflex; the effects were time- and dose-related. Intrathecal pretreatment with mecamylamine, phentolamine or naloxone was without effect. Intrathecal administration of physostigmine, an acetylcholinesterase inhibitor, significantly reduced the threshold intensity of conditioning CRD necessary to inhibit the TF reflex to cut off (mean 36.0 +/- 4.0 mmHg; n = 5). Bilateral transections of the spinal dorsolateral funiculi (DLF) did not affect the inhibitory effect of CRD in 4/7 rats and attenuated the inhibitory effect of CRD in the other 3 rats. The antagonistic effect of methysergide on CRD-produced inhibition of the TF reflex was abolished following the DLF transections, while scopolamine retained its efficacy in rats with bilateral DLF transections. These findings provide evidence for involvement of spinal cholinergic interneurons as well as a descending serotoninergic pathway traveling in the DLF in CRD-produced inhibition of the TF reflex.

Animals↗
PubMed1992

Characterization of descending facilitation and inhibition of spinal nociceptive transmission from the nuclei reticularis gigantocellularis and gigantocellularis pars alpha in the rat.

1. Descending influences produced by focal electrical stimulation in the nuclei reticularis gigantocellularis (NGC) and gigantocellularis pars alpha (NGC alpha) on spinal nociceptive transmission and the dorsoventral region of spinal white matter mediating stimulation-produced modulation were examined in pentobarbital sodium-anesthetized, paralyzed rats. Spinal units studied responded to mechanical stimuli and noxious heating (50 degrees C) of cutaneous receptive fields confined to the glabrous skin of the ipsilateral hind foot. Recording sites were located in laminae I-VI of the L3-L5 spinal segments. 2. Electrical stimulation in the NGC or NGC alpha produced both facilitation and inhibition of responses of spinal units to noxious heating of the skin. At 33 of 57 stimulation sites in the NGC and NGC alpha, electrical stimulation produced biphasic effects, facilitating responses at lesser intensities (5-25 microA) and inhibiting responses at greater intensities (50-100 microA). At 21 other sites in the NGC and NGC alpha, electrical stimulation (5-100 microA) only inhibited, and at 3 sites stimulation (5-100 microA) only facilitated responses of spinal units to noxious heating of the skin. 3. Electrical stimulation in the NGC or NGC alpha contralateral to the spinal recording site produced the same magnitude of facilitation/inhibition or inhibition of spinal nociceptive transmission as did stimulation in the ipsilateral NGC and NGC alpha. 4. The latencies to descending facilitation and inhibition of spinal nociceptive transmission from the NGC and NGC alpha were estimated by a cumulative sum technique to be 232 and 80 ms, respectively. 5. Responses of spinal units to graded heating (42-50 degrees C) of the skin exhibited positively accelerating stimulus-response functions (SRF) throughout the temperature range tested. Electrical stimulation at lesser, "facilitating" intensities produced a parallel, leftward shift of the SRF, whereas stimulation at greater, "inhibitory" intensities significantly decreased the slope of the SRF without affecting the threshold for response. 6. To determine whether activation of cell bodies in the NGC or NGC alpha were capable of replicating the effects of electrical stimulation, L-glutamate was microinjected into sites where electrical stimulation facilitated at lesser and inhibited at greater intensities the responses of spinal units to 50 degrees C heating of the skin. L-Glutamate (5 nmol) produced a rapid onset, short-lasting and reproducible facilitation of nociceptive transmission; glutamate microinjection into the same site at a greater dosage (50 nmol) inhibited responses of the same spinal units.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1991

Spinal serotonin receptors mediate descending facilitation of a nociceptive reflex from the nuclei reticularis gigantocellularis and gigantocellularis pars alpha in the rat.

Electrical stimulation in the nucleus reticularis gigantocellularis (NGC) and gigantocellularis pars alpha (NGC alpha) produces facilitation and/or inhibition of spinal nociceptive transmission in behavioral and electrophysiological studies. The present study examined spinal neurotransmitter receptors mediating descending facilitation from the NGC/NGC alpha. As previously demonstrated, electrical stimulation in the NGC/NGC alpha at low intensities (approximately equal to 10 microA) produced facilitation and at greater intensities (approximately equal to 38 microA) inhibition of the tail-flick (TF) reflex. Intrathecal pretreatment with the non-selective serotonin (5-HT) receptor antagonist methysergide attenuated or completely abolished facilitation of the TF reflex produced by electrical stimulation in the NGC/NGC alpha; intrathecal pretreatment with atropine, phentolamine, naloxone or mecamylamine was without effect on stimulation-produced facilitation. Descending inhibition from the NGC/NGC alpha produced by electrical stimulation was attenuated or completely abolished by bilateral transection of the dorsolateral funiculi (DLF) of the cervical spinal cord. Descending facilitation produced by electrical stimulation, however, was unaffected or enhanced following DLF transections. Glutamate microinjections (1.7 nmol/0.17 microliters) into the NGC/NGC alpha produced a rapid, repeatable and short-duration facilitation of the TF reflex in rats with bilateral DLF transections and such facilitation was attenuated by intrathecal pretreatment with methysergide, but not atropine, xylamidine (5-HT2 selective receptor antagonist) or MDL-72222 (5-HT3 selective receptor antagonist). These findings suggest that facilitation of the TF reflex from the activation of the cell bodies in the NGC/NGC alpha is mediated by a descending serotonergic pathway traveling in the ventrolateral funiculi and by spinal 5-HT1 receptors.

Amidines↗
PubMed1991

Tonic cholinergic inhibition of spinal mechanical transmission.

The present study examined the role of spinal cholinergic modulation of spinal mechanical and thermal transmission. Intrathecal administration of the cholinergic muscarinic receptor antagonists atropine or scopolamine in awake rats produced a dose-dependent decrease in the nociceptive mechanical withdrawal threshold of the rat tail. Pirenzepine, a selective muscarinic receptor type 1 antagonist, produced a similar effect at greater doses while mecamylamine, a nicotinic receptor antagonist, was without effect. The nociceptive tail flick (TF) reflex evoked by noxious heating was unaffected by the above drugs. Intrathecal administration of the cholinesterase inhibitor physostigmine produced a rapid, reversible and significant increase in the mechanical withdrawal threshold; TF latency was increased slightly but not significantly. Intrathecal administration of morphine, carbachol or clonidine all produced dose-dependent increases in TF latency; morphine and carbachol, but not clonidine, also increased the mechanical withdrawal threshold significantly. Intrathecal pretreatment with atropine reversed carbachol-produced increases in TF latency and the mechanical withdrawal threshold but did not affect increases in TF latency produced by intrathecal morphine or clonidine. The morphine-produced increase in the mechanical withdrawal threshold, however, was shifted rightward in a parallel fashion by intrathecal pretreatment with atropine. Intrathecal pretreatment with yohimbine did not affect the inhibitory effect of carbachol on either TF latency or the mechanical withdrawal threshold. These results suggest that a tonic, endogenous cholinergic muscarinic influence in the spinal cord, independent of spinal adrenergic mechanisms, modulates spinal mechanical transmission.

Animals↗
PubMed1990

Spinal cholinergic and monoaminergic receptors mediate descending inhibition from the nuclei reticularis gigantocellularis and gigantocellularis pars alpha in the rat.

Focal electrical stimulation and glutamate microinjection in the nuclei reticularis gigantocellularis (NGC) and gigantocellularis pars alpha (NGC alpha) both inhibit the nociceptive tail-flick (TF) reflex in rats. The present experiments were undertaken to determine the transmitter(s) at the level of the lumbar spinal cord mediating descending inhibition of the TF reflex produced by activation of the NGC/NGC alpha. Intrathecal administration of atropine (7.2-57.6 nmol) produced a dose-dependent increase in the electrical stimulation threshold required for inhibition of the TF reflex. Phentolamine (47.2 or 94.4 nmol) and methysergide (32 or 64 nmol) also increased the stimulation threshold significantly, but only at the greater doses. Neither naloxone (27.5 or 55 nmol) nor mecamylamine (49.1 or 98.2 nmol) affected stimulation thresholds for inhibition of the TF reflex. Stimulation at threshold intensities for inhibition did not change the blood pressure significantly at most sites of stimulation in the NGC/NGC alpha (25/39). Intrathecal administration of atropine, phentolamine or methysergide did not affect resting blood pressure or changes associated with stimulation in most cases, although inhibition of the TF reflex by stimulation in the NGC/NGC alpha was affected consistently by these pretreatments. Similarly, glutamate (100 nmol, 0.5 microliter/1.5 min) microinjection produced a short-lasting inhibition (4.63 +/- 0.70 min, n = 19) of the TF reflex. Glutamate microinjection produced both pressor and depressor effects which were not affected by intrathecal pretreatment. Inhibition of the TF reflex by glutamate was attenuated significantly by intrathecal pretreatment with atropine, scopolamine, phentolamine and methysergide, but not naloxone or mecamylamine. These findings suggest that either a descending or local spinal cholinergic system, together with descending serotonergic and noradrenergic systems, are involved in the centrifugal inhibition of spinal nociceptive transmission from the NGC/NGC alpha.

Animals↗
PubMed1990

Characterization of descending inhibition and facilitation from the nuclei reticularis gigantocellularis and gigantocellularis pars alpha in the rat.

Descending influences on the spinal nociceptive tail-flick (TF) reflex produced by focal electrical stimulation and glutamate microinjection in the nuclei reticularis gigantocellularis (NGC) and gigantocellularis pars alpha (NGC alpha) were examined and characterized in rats lightly anesthetized with pentobarbital. Both inhibition and facilitation of the TF reflex were produced by electrical stimulation at identical sites in the NGC/NGC alpha; glutamate microinjection only inhibited the TF reflex. The chronaxie of stimulation for inhibition of the TF reflex was 169 +/- 28 microseconds. Inhibition of the TF reflex by stimulation was produced throughout the NGC and NGC alpha; intensities of stimulation for inhibition were least in the ventral NGC and in the NGC alpha. At threshold intensities of stimulation, inhibition of the TF reflex did not outlast the period of stimulation. Facilitation of the TF reflex was produced at many of the same sites at which stimulation inhibited the TF reflex, but always at lesser intensities of stimulation (mean, 10 microA vs. 43 microA for inhibition, n = 25). Stimulation in the NGC/NGC alpha at threshold intensities for facilitation or inhibition of the TF reflex did not significantly affect blood pressure. Strength-duration characterization of electrical stimulation and microinjection of glutamate into identical sites in the NGC and NGC alpha suggest that descending inhibition of the TF reflex results from activation of cell bodies in the NGC and NGC alpha.

Animals↗