Biomedical subjects

K Ren

Publications and source records attributed to K Ren.

At least 73 records · Page 4Linked to original sources

PubMed1994

A comparative study of the calcium-binding proteins calbindin-D28K, calretinin, calmodulin and parvalbumin in the rat spinal cord.

Comparison of the immunocytochemical localizations revealed distinct patterns of differential distribution and overlapping of calbindin-D28K (CB-D28K), calretinin (CR), calmodulin (CM) and parvalbumin (PV) in the rat spinal cord. In some areas, one of the four calcium-binding proteins (CBPs) appears to be predominant, for example, CB-D28K in lamina I and ependymal cells, PV at the inner part of laminae II, CR in laminae V and VI and CM in motoneurons of lamina IX. In other regions of the spinal cord, more than one CBPs was abundant. CB-D28K and CR were similarly distributed in lamina II and the lateral spinal and cervical nucleus; CM and PV were similarly abundant in the ventromedial dorsal horn, internal basilar and central cervical nucleus; CR and PV were similarly abundant in the ventromedial dorsal horn, internal basilar and central cervical nucleus; CR and PV were similarly heterogeneous in the gracile fasciculus from caudal to rostral spinal cord. In the sacral dorsal gray commissure, the distribution patterns of CR and PV were clearly complementary. The unilateral ganglionectomies resulted in a substantial reduction of CBP-like immunoreactivity (CBP-LI) in the dorsal columns and a reduction of CM- and PV-LI in the ventromedial dorsal horn. In the motor system, only CM labeled large motoneurons in lamina IX and CB-D28K lightly stained pyramidal tract. The apparent absence of CM-LI in the superficial dorsal horn is contradictory to the presence of a CM-dependent nitric oxide synthase in the region. These data indicate that most CBP-LI in the dorsal column pathway had primary afferent origin, while the superficial dorsal horn exhibited intrinsic CBP immunoreactivity. The differential and selective localizations of CBPs in the spinal cord suggest a role for these proteins in spinal nociceptive processing, visceral regulation and dorsal column sensory pathways.

Animals↗

PubMed1994

Cloning of a DNA binding protein that is a tyrosine kinase substrate and recognizes an upstream initiator-like sequence in the promoter of the preprodynorphin gene.

A 90 bp fragment prepared from the promoter region of the rat preprodynorphin gene formed a complex with rat brain nuclear extracts as assessed by gel mobility shift assays. An 8 base pair sequence, CACTCTCC, termed upstream regulatory element (URE), was identified within this fragment as a binding site by DNase 1 footprint analysis and gel mobility shift assays with synthetic oligonucleotides. The URE is a consensus sequence for a transcription initiator (Inr) element although in the preprodynorphin promoter it is located upstream at -208 and overlaps a region conserved between rat and human promoters. A unique 310 amino acid protein (UreB1) that specifically bound the URE was cloned from a rat brain cDNA library using the URE-containing oligonucleotide. Recombinantly expressed, affinity purified UreB1 protein retains specific binding to the URE oligonucleotide. UreB1 contains a tyrosine kinase phosphorylation consensus and binding is enhanced following phosphorylation with the p43v-abl tyrosine kinase. The UreB1 tyrosine phosphoprotein increases transcription in vitro, consistent with a positive transcriptional regulatory function. UreB1 transcripts are well expressed in subsets of neurons in multiple brain areas suggesting that, in addition to regulation of the preprodynorphin gene, it may have a more generalized role in gene transcription.

Amino Acid Sequence↗

PubMed1993

NMDA receptor antagonists attenuate mechanical hyperalgesia in rats with unilateral inflammation of the hindpaw.

The effects of N-methyl-D-aspartate (NMDA) receptor antagonists on mechanical hyperalgesia associated with tissue inflammation were studied. Following an injection of the inflammatory agent, complete Freund's adjuvant, into the rat hindpaw, there was a significant decrease in threshold and an increase in response duration to mechanical stimuli, suggesting that a state of mechanical hyperalgesia was induced. The intrathecal administration of the NMDA receptor antagonists, dizocilpine maleate and (+/-)-2-amino-5-phosphonopentanoic acid, significantly increased mechanical threshold and reduced response duration in the inflamed hindpaw, but had no effect on the non-injected paw. The results suggest that NMDA receptor activation may contribute to the mechanical hyperalgesia that follows peripheral tissue inflammation.

2-Amino-5-phosphonovalerate↗

PubMed1993

110/140 laminin-binding protein immunoreactivity in spinal dorsal root ganglia: a capsaicin-insensitive reduction induced by constriction injury of the sciatic nerve in rats.

The distribution of 110/140 laminin-binding protein (110/140 LBP) in the spinal dorsal root ganglia (DRG) and its regulation by partial constriction of the sciatic nerve was studied in adult rats. The cross-sectional area of neurons with 110/140 LBP-immunoreactivity (-I) showed an approximately normal frequency distribution. The 110/140 LBP-I was observed in neuronal cell bodies exclusive of the nucleus. Following sciatic nerve constriction, the 110/140 LBP-I was downregulated in the ipsilateral L4-5 DRG. DRG neurons with a cross-sectional area > or = 1600 microns 2 were preferentially affected. Neonatal capsaicin-treatment, a procedure that selectively destroys a subpopulation of DRG neurons with fine unmyelinated axons, had no effect on the reduction of 110/140 LBP in the DRG induced by sciatic nerve constriction. Western immunoblot analysis confirmed a reduction of 110/140 LBP on the side ipsilateral to the constriction. These results demonstrate a LBP within primary sensory neurons and its suppression by peripheral nerve injury. The data support a role for LBP in the adult nervous system.

Animals↗

PubMed1993

Binding of lipoprotein lipase to heparin. Identification of five critical residues in two distinct segments of the amino-terminal domain.

Binding to heparan sulfate governs many aspects of the physiological action and regulation of the lipolytic enzyme, lipoprotein lipase (LPL). In an attempt to identify the structural determinants which mediate this interaction, basic residues in three segments of the primary sequence of human LPL (residues 147-151, 279-282, and 292-304) were replaced with alanine, either singly or in various combinations, and variant proteins were subjected to affinity chromatography on heparin-Superose. Five basic residues in two distinct segments of the primary sequence were critical determinants of the high affinity for heparin manifested by the active enzyme (R279, K280, R282, K296, R297). By contrast, no such evidence could be detected for basic residues in the first cluster (K147, K148) or for other basic residues in the third cluster (K292, R294, K304), while the evidence for K300 was unresolved. The conformation of this heparin-binding domain can be inferred by reference to the three-dimensional structure of the homologous enzyme, pancreatic lipase (Winkler, F. K., D'Arcy, A., and Hunziker, W. (1990) Nature 343, 771-774). Affinity of the active enzyme for heparin could not be reduced below a threshold, suggesting that other heparin-binding determinants exist elsewhere in the molecule, as supported by recently published evidence (Davis, R. C., Wong, H., Nikazy, J., Wang, K., Han, Q., and Schotz, M. C. (1992) J. Biol. Chem. 267, 21499-21504).

Amino Acid Sequence↗

PubMed1993

The effect of cyclosporin A on disease progression in proliferative immune complex glomerulonephritis.

In rats with the proliferative immune complex glomerulonephritis of chronic serum sickness, kidney function deteriorates in three discrete and readily distinguishable stages: Mild, Moderate, and Severe. The mononuclear cell composition of glomerular inflammation is also different in each stage. The immunosuppressive drug, cyclosporin A, was administered to rats with chronic serum sickness in order to investigate the relationship between glomerular immunopathology and pathophysiology in proliferative immune complex nephritis. When introduced after the onset of proteinuria, daily treatment with cyclosporin A failed to prevent the progression from Moderate to Severe nephritis, which is characterized by the abnormal differentiation and local proliferation of glomerular macrophages, as well as grave deterioration in kidney function. In contrast, when cyclosporin A therapy started before the onset of proteinuria, the course of proliferative glomerulonephritis was altered significantly. Although the levels of proteinuria and macrophage accumulation that are characteristic of the Moderate stage of nephritis were not reduced, progression to Severe nephritis did not occur. The number of glomerular macrophages appeared to increase in two separate phases in this chronic serum sickness model of proliferative immune complex glomerulonephritis. The first phase, which coincided with the onset of proteinuria, did not require T cells and culminated only in moderate hypercellularity and proteinuria. The second increase in the number of glomerular macrophages, which was accompanied by the expression of abnormal macrophage phenotypes, was closely linked to the development of severe kidney insufficiency. The protective effect of cyclosporin A therapy was consistent with, although not conclusive proof for, the hypothesis that local T cell activation may contribute to the progression of proliferative immune complex glomerulonephritis. Since cyclosporin A can also directly influence the responses of macrophages and mesangial cells, the effect of the drug on the course of nephritis in this model might not be related to its immunosuppressive action.

Animals↗

PubMed1993

Immunohistochemical localization of calretinin in the dorsal root ganglion and spinal cord of the rat.

Calretinin (CR), a recently identified calcium-binding protein, is present in nervous tissue, including sensory pathways, where it may play an important role in regulation of cellular activity. Using immunocytochemistry, we examined the cellular localization of CR in dorsal root ganglia (DRG) and spinal cord of normal rats and after multiple unilateral dorsal root ganglionectomies. In DRG, CR-immunoreactive cell bodies and axons were a small subpopulation (10%) of medium- to large-sized neurons. In the spinal cord, CR-like immunoreactivity (LI) in neurons and fibers was found in all laminae except motoneurons. Dense fiber networks were also found in Clarke's column. The densest staining of both cell bodies and fibers was in the superficial laminae, especially lamina II, and in the lateral spinal and lateral cervical nuclei. CR-immunoreactive fibers were also observed in the fasciculi cuneatus and gracilis. Fasciculus gracilis exhibited the greatest number of labeled axons at the lumbosacral levels, but few labeled axons were found at the rostral thoracic and cervical levels. In contrast, the corticospinal tract at the base of the dorsal column was devoid of CR-immunoreactive fibers. Unilateral multiple lumbar ganglionectomies resulted in a loss of CR-LI in the dorsal columns ipsilateral to the surgery. In the spinal gray matter ipsilateral to the ganglionectomies, CR-LI was reduced in Clarke's column and slightly enhanced in the medial third of lamina II. Our observations demonstrate a unique distribution pattern of CR-LI compared to other calcium-binding proteins in the spinal cord, and suggest a role for CR in nociceptive and proprioceptive pathways.

Animals↗

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

Synthesis and biological evaluation of novel potent antagonists of the bombesin/gastrin releasing peptide receptor.

This paper reports the synthesis and antagonist activity of 20 C-terminal analogues of gastrin releasing peptide (GRP). The ability of each analogue to inhibit bombesin (BN) stimulated amylase release from rat pancreatic acini was determined, and those showing antagonist activity were further evaluated for their ability to inhibit BN-stimulated [3H]thymidine uptake in serum-starved 3T3 cells. The assays also included two known peptide antagonists, C (Leu14,psi 13,14]BN) and H (N-pivaloyl-GRP20-25-(R)-2-methyl-4-nonylamide) as positive controls. On the basis of these assays we suggest that a des-Met27,Leu26-psi[CH2NHCOCH3]GRP C-terminal octapeptide imparts antagonist activity. The two most active compounds are peptides 14 ([D-Phe19,Leu26-psi(CH2NHCOCH3)]GRP19-26) and 18 ([D-Phe19,Gln20,Leu26-psi(CH2NHCOCH3)]GRP19++ +-26). In their ability to inhibit BN-stimulated [3H]thymidine uptake, the IC50 of peptides C, H, 14, and 18 were 43.2, 31.2, 2.7, and 32.5 nM, respectively. In conclusion, the novel C-terminal psi[CH2NHCOCH3] bond promises to be a useful peptide backbone modification for imparting antagonism in GRP/BN analogues.

Amino Acid Sequence↗

PubMed1992

The intrathecal administration of excitatory amino acid receptor antagonists selectively attenuated carrageenan-induced behavioral hyperalgesia in rats.

A single unilateral injection of carrageenan (4.5-6.0 mg in 0.15-0.20 ml saline) into the rat hindpaw induced behavioral hyperalgesia as evidenced by a significant reduction in hindpaw withdrawal latency to a noxious thermal stimulus. The involvement of N-methyl-D-aspartate (NMDA) receptors in this model of hyperalgesia was examined by intrathecal administration of the selective excitatory amino acid (EAA) receptor antagonists: (+/-)-2-amino-5-phosphonopentanoic acid (AP-5), (+/-)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP), ketamine hydrochloride (ketamine), 7-chlorokynurenic acid (7-Cl kynurenic acid), and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). The effects of dizocilpine maleate (MK-801) were studied under the same conditions and published previously (Ren et al., 1992) and the data are presented for comparison. While the withdrawal latencies of the non-injected paws and of the paws of naive rats were not significantly affected by application of the EAA receptor antagonists at doses tested, the paw withdrawal latencies of the carrageenan-injected paws were elevated dose dependently. The rank order of potency of these agents to reduce hyperalgesia was: MK-801 greater than or equal to AP-5 greater than or equal to CPP = 7-Cl kynurenic acid = ketamine much greater than CNQX greater than 0. In contrast, intrathecal injection of the opioid receptor agonists, [D-Ala2,MePhe4,Gly-ol5]enkephalin (DAMGO, mu-selective) and [D-Pen2,D-Pen5] enkephalin (DPDPE, delta-selective), produced antinociception in both injected and non-injected paws. DAMGO was much more potent, while DPDPE was less potent, than MK-801.(ABSTRACT TRUNCATED AT 250 WORDS)

6-Cyano-7-nitroquinoxaline-2,3-dione↗

PubMed1991

Effects of electrical stimulation of vagal afferents on spinothalamic tract cells in the rat.

The effects of electrical stimulation of cervical vagal afferents (VAS) on the background activity and on the responses of 25 spinothalamic tract (STT) neurons to noxious stimuli were studied in anesthetized rats. Background (spontaneous) activity of 9 (36%) STT neurons was inhibited by all intensities of VAS. 6 (24%) units were facilitated at lesser and inhibited at greater intensities of VAS, 5 (20%) units were only facilitated by all intensities of VAS, and 5 (20%) units were not affected by VAS. Responses of 8 (36%) STT neurons to noxious stimuli were only inhibited by VAS, 9 (41%) were facilitated at lesser and inhibited at greater intensities of VAS, and 5 units (23%) were only facilitated by VAS. There were no significant differences in VAS-produced modulatory effects between STT neurons and 16 unidentified lumbar spinal dorsal horn neurons studied under the same conditions. These results reveal that descending facilitatory and inhibitory pathways engaged by activation of vagal afferents modulate rostrally projecting nociceptive transmission neurons in the spinal cord, constituting an important regulatory network for nociception.

Anesthesia↗

PubMed1990

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.

Animals↗

PubMed1990

Mononuclear cells in glomeruli and cytokines in urine reflect the severity of experimental proliferative immune complex glomerulonephritis.

Immunohistochemical methods were used to investigate the role of macrophages in the progression of proliferative immune complex glomerulonephritis. The mononuclear cell component of glomerular inflammation was analysed in three different stages of chronic serum sickness, each of which was clearly distinguished by criteria of kidney function. Urinary excretion of the macrophage secretory products interleukin-1 and tumour necrosis factor was also evaluated in relation to the functional severity of kidney disease. T lymphocytes and macrophages began to accumulate in glomeruli at the onset of proteinuria, but not before. Urinary excretion of interleukin-1 also began with proteinuria. Proteinuria increased in direct correlation with increases in the number of glomerular macrophages. Development of the most severe stage of glomerulonephritis, characterized by cachexia, declining kidney function, and necrotizing glomerular pathology, was accompanied by the disappearance of T cells from glomeruli and the expression of highly abnormal phenotypes by most macrophages. In addition, there was a switch from urinary excretion of interleukin-1 to excretion of tumour necrosis factor. The progression of proliferative immune complex glomerulonephritis was associated with qualitative as well as quantitative changes in glomerular macrophage populations. Differentiation and/or activation of those glomerular macrophages may have resulted from local T cell-mediated immunoregulation. Measurements of urinary cytokine excretion provided a reliable means of monitoring disease progression. The local action of tumour necrosis factor probably contributed to declining kidney function in the most severe stage of disease.

Animals↗

PubMed1990

Modulation of spinal nociceptive transmission from nuclei tractus solitarii: a relay for effects of vagal afferent stimulation.

1. The effects of electrical and chemical stimulation in the nucleus tractus solitarii (NTS) on spinal nociceptive transmission were examined in pentobarbital sodium-anesthetized, paralyzed rats. These studies also examined the role of the NTS as a relay for the effects of vagal afferent stimulation (VAS) on spinal nociceptive transmission. All 75 neurons studied were located in laminae I-VI in the L3-L5 spinal segments, with receptive fields on the glabrous skin of the plantar surface of the ipsilateral hindpaw. The units responded to mechanical (low and/or high intensities) and thermal stimuli (42-52 degrees C). 2. Electrical stimulation in the NTS either ipsilateral or contralateral to the spinal unit inhibited neuronal responses to noxious thermal stimuli. The magnitude of inhibition did not significantly differ as a function of either ipsilateral (15 units) or contralateral (12 units) NTS stimulation (NTSS) as indicated by extrapolated thresholds for inhibition of responses to heat, intensities to produce 50% inhibition of responses to heat, and the slope of recruitment lines for inhibition. Tracking experiments also revealed that stimulation in the area ventral to the NTS produced a greater magnitude of inhibition of these units than did NTSS. 3. NTSS significantly decreased the slope of the stimulus-response functions (SRFs) of dorsal horn units to graded thermal stimuli (42-52 degrees C), whereas response threshold was unaffected by NTSS. The apparent latency of NTSS to produce inhibition of unit responses to heating of the hindpaw was determined to be 50 +/- 10 ms (mean +/- SE). 4. Microinjection of 50 nmol of glutamate into the NTS ipsilateral to the spinal unit also inhibited neuronal responses to thermal stimuli in 17/21 units; responses of 2/21 units were facilitated. Inhibition typically lasted 4-7 min and was shown to be dose-volume dependent. 5. The effects of VAS and NTSS on spinal nociceptive transmission were directly compared. The responses of 17 units to 50 degrees C heating of the hindpaw were facilitated by low and inhibited by greater intensities of VAS (Biphasic units); the responses of 12 units were only inhibited by VAS (Inhib units); three were only facilitated (Facil units), and 2 were unaffected by VAS. In contrast, NTSS generally inhibited the same spinal units, although modest facilitation was produced by NTSS contralateral to the recording site. NTSS produced greater inhibition of the Biphasic units than did VAS, shown by a leftward shift of the recruitment line of inhibition and greater inhibition at the same intensity of electrical stimulation.(ABSTRACT TRUNCATED AT 400 WORDS)

Action Potentials↗

PubMed1990

Electrical stimulation of cervical vagal afferents. I. Central relays for modulation of spinal nociceptive transmission.

1. Supraspinal relays for vagal afferent modulation of responses of spinal dorsal horn neurons to 50 degrees C heating of the skin were examined by the use of nonselective, reversible local anesthesia or soma-selective, irreversible neurotoxic damage of neural tissue. Eighty-five neurons were isolated in the lumbar spinal dorsal horn of 80 pentobarbital-anesthetized, paralyzed rats. All neurons studied had receptive fields on the glabrous skin of the plantar surface of the ipsilateral hind paw and responded to mechanical stimuli of both low and high intensity as well as noxious thermal stimulation. 2. Intensity-dependent modulation by vagal afferent stimulation (VAS) of neuronal responses to heating of the skin was established. Responses of 40 units were facilitated by low and inhibited by greater intensities of VAS. Another 36 units were only inhibited by VAS, and four were only facilitated. 3. Local anesthesia of the dorsolateral pons by bilateral microinjections of lidocaine (4%, 0.5 microliter) were made to examine the contribution of this area to VAS-produced spinal modulation. The microinjection of lidocaine bilaterally into the ventral locus coeruleus/subcoeruleus (LC/SC) reversibly and significantly attenuated VAS-produced inhibition of unit responses to heat from 63 to 89% of control and abolished VAS-produced facilitation. The microinjection of lidocaine bilaterally into the dorsal LC had no significant effect on VAS-produced modulation of spinal dorsal horn neurons. 4. Ibotenic acid (10 micrograms, 0.5 microliter) was microinjected into the dorsolateral pons to determine the relative contributions of cell bodies in this area to VAS-produced spinal modulation. Unilateral microinjection of ibotenic acid into the LC/SC ipsilateral to the vagus nerve stimulated had no significant effect on VAS-produced inhibition but significantly attenuated VAS-produced facilitation of unit responses to heat. Bilateral microinjections of ibotenic acid significantly attenuated VAS-produced inhibition of unit responses to heat from 48 to 94% of control. 5. Local anesthesia of the medial rostroventral medulla (RVM), primarily the nucleus raphe magnus (NRM), significantly attenuated VAS-produced inhibition of unit responses to heat from 55 to 87% of control but had no significant effect on VAS-produced facilitation. Microinjection of ibotenic acid into the RVM also significantly reduced VAS-produced inhibition of unit responses to heat. No significant change in VAS-produced spinal modulation was found after lidocaine microinjection into areas dorsal to the NRM, the nucleus raphe pallidus, or the olivary nucleus.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1990

Electrical stimulation of cervical vagal afferents. II. Central relays for behavioral antinociception and arterial blood pressure decreases.

1. Supraspinal substrates mediating vagal afferent stimulation (VAS)-induced inhibition of the nociceptive tail-flick reflex were examined by the use of the soma-selective neurotoxin ibotenic acid and the nonselective local anesthetic lidocaine. Fifty rats were studied in the lightly anesthetized state maintained with pentobarbital sodium. 2. The threshold intensity of VAS required to inhibit the tail-flick reflex to a cut-off latency of 10 s was established in all rats. Ibotenic acid (5 or 10 micrograms, 0.5 microliter) or lidocaine (4%, 0.5 microliter) was then microinjected into various regions of the brain stem followed by reestablishment of the intensity of VAS required to produce inhibition of the tail-flick reflex. 3. Microinjections of ibotenic acid into the ipsilateral nucleus tractus solitarius (NTS), medial rostroventral medulla (principally the nucleus raphe magnus; NRM), or bilaterally into the dorsolateral pons (principally the locus coeruleus/subcoeruleus; LC/SC), significantly increased the threshold intensity of VAS required to inhibit the tail-flick reflex. Microinjections of ibotenic acid into either the rostral or caudal ventrolateral medulla (RVLM or CVLM, respectively) ipsilateral to the vagus nerve stimulated or ipsilateral LC/SC did not significantly affect the inhibition produced by VAS. Arterial blood pressure decreases produced by VAS were significantly attenuated or eliminated after microinjections of ibotenic acid into the NTS, RVLM, CVLM, or NRM. Lidocaine microinjected into the ipsilateral CVLM also significantly increased the intensity of VAS required to inhibit the tail-flick reflex. 4. These outcomes obtained with behavioral measures are consistent with the outcomes of the preceding study using electrophysiological measures in establishing that cells in the NTS, LC/SC, and NRM regions and fibers of passage in the CVLM are important in mediating the inhibitory effects of VAS. The present studies confirm previous reports of the importance of the RVLM and CVLM in VAS-produced depressor responses but also demonstrate that the NRM is critical for this cardiovascular response.

Animals↗

PubMed1989

Vagal afferent modulation of spinal nociceptive transmission in the rat.

1. The effects of vagal afferent stimulation (VAS) on spinal nociceptive transmission and the spinal pathway(s) mediating VAS-produced effects were examined in pentobarbital sodium- and urethane-anesthetized, paralyzed rats. The 60 units studied responded to mechanical stimuli and noxious heating (50 degrees C) of cutaneous receptive fields confined to the glabrous skin of the toes and footpads. Recording sites were located in laminae I-VI of the L3-L5 spinal segments. 2. VAS facilitated and inhibited neuronal responses to heat. In pentobarbital-anesthetized rats, responses of most (24/44) units were facilitated by low and inhibited by higher intensities of VAS. Responses of some units (15/44) were only inhibited and others (4/44) only facilitated by VAS. Inhibition produced by VAS was intensity-, pulse width-, frequency-, and stimulation duration-dependent. In urethane-anesthetized rats, responses of 6/16 units were initially facilitated, then inhibited as the intensity of VAS was increased; responses of nine units were inhibited by VAS. Quantitative comparisons of recruitment indices, mean thresholds for inhibition and mean intensities to inhibit unit responses to heat to 50% of control revealed no significant differences between the two anesthetic conditions. 3. The effects of VAS on neuronal responses to heat were dissociable from its effect on blood pressure. Regardless of the effect of VAS on unit responses to noxious heat, VAS consistently produced intensity-dependent depressor responses. The latencies to onset of inhibition and facilitation by VAS were determined by a cumulative sum technique and bin-by-bin analysis of peristimulus time histograms. The apparent latencies were 91 +/- 11 (SE) ms for inhibition and 278 +/- 59 ms for facilitation, both of which occurred before changes in blood pressure. Finally, microinjections of lidocaine into the ventrolateral funiculus (VLF) or transections of the dorsolateral funiculus (DLF) of the thoracic spinal cord attenuated VAS-produced effects on neuronal responses, but did not affect VAS-induced depressor responses. 4. The responses of 11 dorsal horn units to graded noxious heating of the skin were studied; the stimulus-response functions (SRF) were linear and monotonic throughout the temperature range examined (42-52 degrees C). VAS at intensities which inhibited unit responses to heat significantly decreased the slope of the SRF. VAS at intensities which facilitated unit responses to heat produced a leftward, parallel shift of the SRF.(ABSTRACT TRUNCATED AT 400 WORDS)

Afferent Pathways↗

PubMed1988

Vagal afferent modulation of a nociceptive reflex in rats: involvement of spinal opioid and monoamine receptors.

Modulation of the spinal nociceptive tail flick (TF) reflex by electrical stimulation of subdiaphragmatic or cervical vagal afferent fibers was characterized in rats lightly anesthetized with pentobarbital. Cervical vagal afferent stimulation (VAS) inhibited the TF reflex in a pulse width-, frequency-, and intensity-dependent fashion. The optimum parameters for inhibition of the TF reflex were determined to be 2.0 ms pulse width, 20 Hz frequency with a threshold (T) current of 60 microA. Cervical VAS at 0.2-0.6 T facilitated the TF reflex. Cervical VAS at T typically produced a depressor arterial blood pressure response, but inhibition of the TF reflex by VAS was not due to changes in blood pressure. Subdiaphragmatic VAS also inhibited the TF reflex and generally produced a pressor effect, but did not facilitate the TF reflex at intensities of stimulation less than T as did cervical VAS. The parameters of cervical VAS required for inhibition of TF reflex suggest that excitation of high-threshold, unmyelinated fibers are important in VAS-induced descending inhibition. The intrathecal administration of pharmacologic receptor antagonists into the subarachnoid space of the lumbar enlargement indicated that the opioid receptor antagonist naloxone produced a dose-dependent antagonism of cervical VAS-produced inhibition of TF reflex, but single doses of either phentolamine or methysergide (30 micrograms each) failed to affect the inhibition by VAS. Combined intrathecal injection of both phentolamine and methysergide (30 micrograms each), however, significantly attenuated inhibition of the TF reflex by cervical VAS. These results suggest that cervical VAS engages a spinal opioid system and co-activates descending serotonergic and noradrenergic systems to modulate spinal nociceptive processing.

Afferent Pathways↗