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Biomedical subjects

K Yashpal

Publications and source records attributed to K Yashpal.

At least 19 recordsLinked to original sources
PubMed1992

Quantitative autoradiographic distribution of calcitonin gene-related peptide (hCGRP alpha) binding sites in the rat and monkey spinal cord.

Calcitonin gene-related peptide (CGRP) has been implicated in various spinal functions on the basis of its presence in the substantia gelatinosa and motoneurons and the biological effects induced by intrathecal CGRP injections. We investigated here the comparative distribution of [125I]hCGRP alpha binding sites in various segments of the rat and monkey spinal cord. The immunocytochemical localization of CGRP-like material in rat spinal cord was also evaluated for comparison. In the rat spinal cord, high densities of [125I]hCGRP alpha binding sites were observed in lamina I, in a U-shaped band that included lamina X and the medial parts of laminae III-IV and in the intermediolateral and intermediomedial nuclei. The substantia gelatinosa (lamina II) contained relatively lower, but still significant, densities of [125I]hCGRP alpha binding sites, while the ventral horn showed low amounts of specific labeling. CGRP-like immunoreactive fibers, on the other hand, were heavily concentrated in laminae I-II and in the reticulated portion of lamina V of the dorsal horn. Immunoreactivity to CGRP antiserum was also noted in fibers around the central canal and in a number of motoneurons of the ventral horn. In the monkey spinal cord, [125I]hCGRP alpha binding sites were present in lamina I in a U-shaped band that included lamina X and the medial portions of laminae V-VI. Relatively low levels of [125I]hCGRP alpha binding were detected in laminae II to IV of the dorsal horn, while the ventral horn was more enriched with specific [125I]hCGRP alpha binding sites. Thus, it appears that the autoradiographic distribution of [125I]hCGRP alpha sites is species dependent in the spinal cord. Additionally, some differences are observed between the localization of [125I]hCGRP alpha binding sites and immunoreactive material in the rat spinal cord. These differences may be relevant to the purported roles of CGRP-like peptides in spinal functions such as nociception, control of sympathetic output, and motor control.

Animals↗
PubMed1992

Adenosine receptor link in an adrenal opioid-induced antinociception in the rat tail-flick test.

Intrathecal administration of substance P at the lower thoracic spinal level has an antinociceptive effect on reaction time in the tail-flick test; this response is blocked by naloxone i.v. but not by i.v. administration of opiate antagonists which do not cross the blood-brain barrier. As morphine-induced analgesia is blocked by adenosine antagonists, to determine whether this substance P-induced, opioid-mediated antinociception also includes a purine link, the adenosine receptor antagonist, caffeine, was given systemically 10 min prior to substance P administration. In control rats pretreated with saline, substance P (6.5 nmol) produced an increase in reaction time to about 160% of preadministration values at one min after intrathecal injection. The effect could also be observed at 6 min after this injection. Pretreatment with 16 or with 32 mg/kg of caffeine i.p. blocked the response to substance P, and produced a hyperalgesia similar to that reported in studies at the lumbo-sacral spinal level. These results indicate that the adrenal opioid-induced antinociception observed upon intrathecal administration of substance P at the lower thoracic level occurs via an adenosine link. This is the first demonstration of a purine link in the expression of antinociceptive effects of an endogenously released opioid.

Adenosine↗
PubMed1991

NMDA receptor antagonist blocks the facilitation of the tail flick reflex in the rat induced by intrathecal administration of substance P and by noxious cutaneous stimulation.

This study examined effects of the N-methyl-D-aspartate (NMDA) receptor antagonist, 2-amino-5-phosphonovaleric acid (APV), on facilitation of the tail flick reflex (1) by intrathecal administration of 6.5 nmol of substance P at the lumbar spinal level in awake rats and (2) by noxious cutaneous stimulation in anesthetized rats (by immersing the tip of the tail in hot water at 55 +/- 1 degrees C for 1.5 min). Reaction time was decreased by about 70% by intrathecal administration of substance P and by about 40% by tail immersion. Intrathecal administration of APV (2 nmol) or cerebrospinal fluid (CSF) failed to alter the baseline responses. However, APV but not CSF blocked the facilitation induced by intrathecal administration of substance P and by tail immersion. These results indicate that while NMDA receptors do not appear to be involved in mediating the tail flick reflex, they may be involved in expression of the facilitation of this reflex by substance P and/or by a related peptide.

2-Amino-5-phosphonovalerate↗
PubMed1991

Effects of dorsal rhizotomy on neurokinin receptor sub-types in the rat spinal cord: a quantitative autoradiographic study.

Although abundant evidence suggests a major role for substance P (SP) and other neurokinins (NK) in the transmission of nociceptive information, it is not known whether the various NK receptor classes are differentially located in the substantia gelatinosa of the spinal cord where primary afferent fibres mostly terminate. In order to investigate this issue, we studied the effects of unilateral dorsal rhizotomy on binding of 125I-Bolton-Hunter-SP, (2-[125I]iodohistidyl1)-neurokinin A, and 125I-Bolton-Hunter-eledoisin as respective radioligands for the NK-1, NK-2 and NK-3 receptor sub-types. Seven, 14, 21 and 28 days following unilateral lumbosacral dorsal horn deafferentiation, NK receptor binding parameters were evaluated using quantitative receptor autoradiography. Rhizotomy produced an increase in the densities of NK-1, NK-2 and NK-3 binding sites in the superficial laminae of the dorsal horn. Increases were maximal at 14 days, post-operatively, for both NK-1 and NK-2 sites; slight recovery being observed thereafter. For NK-3 sites, unilateral rhizotomy induced a progressive increase in binding without evidence of recovery over time, at least up to 28 days post-lesion. NK-1 receptor binding parameters around the central canal and in the ventral horn were not affected by the dorsal rhizotomy. These data suggest that all 3 NK receptor classes are located post-synaptically to afferent fiber terminals in laminae I, II and X of the dorsal horn of the spinal cord.

Analysis of Variance↗
PubMed1990

Quantitative autoradiographic distribution of multiple neurokinin binding sites in rat spinal cord.

As a means of evaluating the role of neurokinins (NKs) in spinal function, the present study examines the quantitative autoradiographic distribution in the rat spinal cord of [125I]Bolton-Hunter-substance P, (2-[125I]iodohistidyl1)-neurokinin A and [125I]Bolton-Hunter-eledoisin as respective radioligands for NK-1, NK-2 and NK-3 receptors. These putative NK receptor sub-types are clearly differentially distributed at the various levels of the spinal cord. NK-1 sites represent the most abundant population of spinal NK receptors. They are most concentrated in the dorsal and ventromedial borders of the dorsal horn, the intermediolateral nucleus of the thoracic cord and the phrenic motor nucleus in the cervical ventral horn. NK-2 and NK-3 sites are also present in the spinal cord, although in much lower quantities than NK-1 sites. NK-2 sites are mostly found along the dorsal and ventromedial borders of the dorsal horn, in a narrow band connecting the two lateral horns of the thoracic cord, around the central canal of the lumbar and sacral segments and lamina IX of the cervical ventral horn. NK-3 sites are most dense in the dorsal border of the dorsal horn, with moderate amounts in the lateral horn of the thoracic cord and around the central canal of lumbar and sacral segments. The differential distribution of these 3 classes of NK sites in the spinal cord suggests that each NK receptor sub-type could mediate specific sensory, autonomic and/or motor functions at the spinal level.

Animals↗
PubMed1990

Intrathecal administration of calcitonin gene-related peptide (CGRP) increases heart rate and decreases arterial pressure in the urethane anesthetized rat.

Intrathecal administration of CGRP (2.15-8.60 nmol) to the ninth thoracic vertebral segment of the spinal cord in the urethane anesthetized rat provoked an increase in heart rate (peak effect of 72 bpm) and a decrease in arterial pressure (maximum fall of 15 mmHg). Administration of CGRP to the T2 level (n = 10) or intravenously (n = 6) produced qualitatively and quantitatively similar effects to those observed following administration to the T9 level. The drop in pressure resulting from intrathecal administration was unaffected by prior intrathecal administration of lidocaine (250 micrograms), systemic administration of hexamethonium (5 mg/rat), bilateral vagotomy, or combined bilateral vagotomy/hexamethonium treatment. The failure of these manipulations to alter the hypotension induced by intrathecal CGRP injection suggests that this effect was caused by leakage into the periphery. The cardioacceleration elicited by intrathecal CGRP was attenuated by intrathecal lidocaine administration and by combined bilateral vagotomy/hexamethonium treatment, but not by either treatment alone. These results suggest that CGRP's tachycardic effect is mediated by a direct spinal action involving both sympathetic and parasympathetic mechanisms.

Animals↗
PubMed1989

Cardiovascular responses to intrathecal administration of strychnine in the rat.

Experiments were done to determine the influence of spinal glycinergic mechanisms in regulating sympathetic output to the heart and vessels in the anaesthetized male Sprague-Dawley rat. Intrathecal administration of 65 (n = 6) and 130 (n = 8) nmol of strychnine, but not of a lower dose (32.5 nmol, n = 8), to the second thoracic segment increased heart rate within one minute (P less than 0.01). Similar administration of artificial cerebrospinal fluid (n = 16) had no effect. The increase in heart rate in response to strychnine peaked at 5-7 min (+35.1 +/- 5.8 bpm with 130 nmol), and slowly returned toward baseline values over the next 25 min. Arterial pressure was unaffected by this treatment. These effects were not mimicked by administration of strychnine (n = 6) at the third lumbar spinal level or by intravenous infusion of strychnine (n = 4) and were abolished by systemic injection of hexamethonium (n = 6). The results suggest that there is a tonic glycine-mediated inhibition of sympathetic output at the spinal level.

Adrenergic Fibers↗
PubMed1989

Angiotensin II stimulates sympathetic output by a direct spinal action.

When administered intrathecally in a dose of 10 mu to the ninth thoracic segment of the spinal cord in the anesthetized rat, angiotensin II produced a transient increase in systolic and diastolic arterial pressures lasting 1-4 min. Heart rate was also increased, but in this case for more than 30 min. Similar administration of 5 micrograms or of CSF had no effect on either arterial pressure or heart rate. Neither the arterial pressure nor the heart rate response to 10 micrograms of angiotensin II was observed in rats given hexamethonium (10 mg/kg, i.v.), suggesting that the effects were mediated by spinal activation of sympathetic output. When the rats were pretreated with 10 micrograms of [Sar1, IIe8]-angiotensin II three min prior to angiotensin II, there was a block of the increase in arterial pressure but not of the increase in heart rate. When the antagonist was given 15 min prior to angiotensin II, the full pressor response appeared, suggesting that the antagonist was effective for less than 15 min; in addition, after the antagonist alone, while arterial pressure remained unaltered, there was a gradual increase in heart rate suggesting that the analogue had agonistic effects on mechanisms regulating heart rate. These results suggest that angiotensin II activates sympathetic mechanisms by a spinal action and that arterial pressure and heart rate are regulated differentially, arterial pressure via a mechanism which is antagonized by [Sar1, IIe8]-angiotensin II, and heart rate via a mechanism in which the analog can act as an agonist.

Angiotensin II↗
PubMed1989

Thyrotropin-releasing hormone given intrathecally to the rat increases arterial pressure and heart rate.

In view of evidence implicating thyrotropin-releasing hormone (TRH) as a chemical mediator of synaptic transmission onto spinal sympathetic neurons, this peptide was administered intrathecally, in a dose of 6.5 nmol, at the T9 and T2 spinal levels in the anesthetized rat. At the lower thoracic level TRH increased arterial pressure and heart rate; these effects peaked at 4-7 minutes and decayed over the next 15-20 minutes. At the upper thoracic level the pressor and cardioacceleratory responses were roughly similar in time course but were smaller in magnitude. Hexamethonium (10 mg/kg i.v.) was tested on the responses from the lower thoracic level; both pressor and cardioacceleratory responses persisted after hexamethonium pretreatment. In addition, intravenous administration of 6.5 nmol of TRH failed to alter arterial pressure or heart rate, suggesting that the effects produced by the intrathecal administration of TRH were due to an action of the peptide in the spinal cord. The results also indicate that the pressor effect and the increase in heart rate may be mediated in the sympathetic ganglia at least partly via nonnicotinic transmission. Our results provide physiological support for the possibility that TRH is a chemical mediator of synaptic transmission onto sympathetic preganglionic neurons. This study indicates that the functional sympathetic pathways utilizing TRH as a chemical mediator include those regulating arterial pressure and heart rate.

Animals↗
PubMed1987

Substance P given intrathecally at the spinal T9 level increases arterial pressure and heart rate in the rat.

Administration of 10 micrograms of substance P intrathecally at the spinal T9 level of the unanaesthetized and the anaesthetized rat provoked an increase in arterial pressure and an increase in heart rate. Both cardiovascular responses began within 1-2 min of administration, and the peak of each occurred at 4-10 min. In the anaesthetized rat, which gave rise to the bulk of the responses reported, peak arterial pressure was ca 20 mm Hg greater than pre-administration levels, and peak heart rate was greater by ca 50 beats per min. Similar administration of vehicle failed to alter either parameter. Arterial pressure and heart rate in substance P-treated rats were significantly different from those in vehicle-treated rats up to 15-20 min after administration. Pretreatment with the sympathetic ganglion blocker, hexamethonium (10 mg/kg, i.v.), prevented the responses to intrathecal administration of substance P. Pretreatment with [D-Pro2, D-Phe7, D-Trp9]-substance P, an analogue with antagonist properties in the central nervous system, blocked both responses to substance P but failed to alter similar responses provoked by intrathecal administration of angiotensin II. Pretreatment with vehicle had no effect on responses to substance P or to angiotensin II. The antagonist also had partial agonistic effects. Both arterial pressure and heart rate were transiently increased, but this effect was reversed within 6 min; in the case of heart rate, values returned to the pre-application level but arterial pressure fell to a ca 15 mm Hg below this level. These results demonstrate a pharmacologically specific excitatory effect of substance P on spinal mechanisms controlling sympathetic output to the vessels and the heart; this output can be either via the adrenal medullae or via nerve pathways to the vessels and the heart. Our results also support the possibility that dysfunction of substance P systems at the spinal level may underly some models of hypertension and may be involved in some cases of essential hypertension in man, as well as in autonomic dysfunction associated with some neurological disorders.

Anesthetics↗
PubMed1987

Oxytocin administered intrathecally preferentially increases heart rate rather than arterial pressure in the rat.

Oxytocin was administered intrathecally at a dose of 6.5 nmol to the 9th or 2nd thoracic level of the spinal cord in the rat. This increased heart rate but had no effect on arterial pressure. The increase in heart rate began within 1 and 5 min and reached a peak at 10-30 min; the maximum increase, at 10 min after administration, at the second thoracic level was 65.4 +/- 13.8 (S.E.M.) bpm (n = 9). When administration was at the 9th thoracic level the change at 10 min was 36.9 +/- 18.0 bpm (n = 14). Administration of hexamethonium systematically, to block nicotinic transmission in autonomic ganglia, prevented the cardioacceleration in response to intrathecal administration of oxytocin. When 6.5 nmol of oxytocin were administered i.v., there was an immediate decrease in heart rate by 42.5 +/- 16.5 bpm (n = 4) and an increase in systolic (6.3 +/- 6.4 mm Hg) and in diastolic (38.8 +/- 8.3 mm Hg) pressures (n = 4); this effect lasted 5-10 min. Administration of 1.625 nmol of oxytocin at the 9th thoracic level had an effect qualitatively similar to that seen with the higher dose, but the response was smaller in magnitude and more delayed in onset; 0.65 nmol of oxytocin were without effect. Transfer of label to the blood after intrathecal administration of [125I]oxytocin indicated that the level in the blood reached a maximum of 0.6% of the total injected by 30 min after administration. It is concluded that the intrathecal administration of reached a maximum of 0.6% of the total injected by 30 min after administration. It is concluded that the intrathecal administration of oxytocin increases heart rate via an action in the spinal cord, presumably on sympathetic preganglionic neurons. Our results are consistent with earlier suggestions that oxytocin may be a chemical mediator of synaptic transmission onto sympathetic preganglionic neurons.

Animals↗
PubMed1985

Characterization of spinal actions of four substance P analogues.

Four substance P (SP) analogues were tested on reaction time (RT) in the tail flick test and on the decrease in RT produced by the SP homologue physalaemin. The four analogues were [D-Trp7,9,10]SP, denoted A, [D-Pro4,D-Trp7,9,Nle11]SP-(4-11), denoted B, [D-Pro2,D-Trp7,9,10]SP, denoted C and [D-Pro4,D-Trp7,9,10,Phe11]SP-(4-11), denoted D. Physalaemin alone (1.89 nmol) reduced RT. The analogue A, at 3.25 nmol, blocked the effects of physalaemin without altering basal RT. The analogues B and D, which block the action of physalaemin in peripheral tissues, had neither agonistic nor antagonistic effects in doses up to 6.5 nmol. The replacement of L-Pro2 by D-Pro2 in the analogue A yielded the analogue C, which had no antagonistic activity. All analogues produced a flaccid paralysis of the hindlimbs and the tail; this effect was inconsistent, though, occurring only in some rats, and appearing in some cases after the first administration of the analogue yet in other cases only after a subsequent administration. Because B and D are inactive in the spinal cord, our results suggest that physalaemin activates receptors in the spinal cord different from those it activates in peripheral tissues. Furthermore, because all four analogues produced a flaccid paralysis none is suitable for use as an SP antagonist in vivo in the CNS.

Animals↗
PubMed1985

Substance P given intrathecally at the spinal T9 level increases adrenal output of adrenaline and noradrenaline in the rat.

Administration of 10 micrograms of substance P intrathecally to the spinal T9 level of the adult rat, anaesthetized with urethane, provoked an increase in free catecholamines in plasma taken from the inferior vena cava. Adrenaline levels at 1 min after administration were 154.8 +/- 10.8% (mean +/- SE; n = 11) of preadministration levels and noradrenaline levels were 153.5 +/- 11.8% of preadministration levels. Differences between the values of free catecholamines in animals given substance P vs those given vehicle only were statistically significant at 1 and 10 min postinjection, but not at 30 min. Administration of a substance P analogue with central antagonistic properties 15 min before substance P was given prevented expression of the effects of substance P. These results suggest that substance P may be an excitatory chemical mediator of synaptic transmission in spinal pathways controlling adrenal medullary output. Thus dysfunction of substance P mechanisms may underlie some animal models of hypertension and may be involved in some cases of essential hypertension in man as well as in autonomic dysfunction associated with some neurological entities.

Adrenal Medulla↗
PubMed1984

Substance p analogue blocks sp-induced facilitation of a spinal nociceptive reflex.

Intrathecal administration of 10 micrograms (6.5 nmoles) of substance P to the lumbar spinal cord of the awake, restrained rat had a biphasic effect on reaction time in the tail-flick test. This effect consisted of an initial decrease at one min after administration, followed five min later by a smaller increase in reaction time. When substance P was given after prior intrathecal administration of 1.55, 3.1 or 6.2 nmoles of [D-Pro2, D-Phe7, D-Trp9]-substance P, the reduction in latency could be blocked in a dose-related manner. The analogue alone failed to alter reaction time but did produce a flaccid paralysis in some cases. Our results support the possibility that substance P is involved in transmission of nociceptive information at the spinal level, but indicate that it does not participate directly in the fast tail withdrawal response. The mechanism of the flaccid paralysis is not understood, but it appears to be a cumulative effect of more than one dose and is likely associated with motor rather than sensory neurones.

Animals↗
PubMed1983

Endorphins mediate overshoot of substance P-induced facilitation of a spinal nociceptive reflex.

In the awake restrained rat the intrathecal administration of substance P to the lumbar spinal cord abruptly but transiently reduces reaction time in the tail-flick test. Interestingly, this hyperalgesic effect is followed by an increased response time, i.e., a hypoalgesia, which lasts less than 10 min. Administration of naloxone reduces the reaction time. It leaves the initial hyperalgesia unaltered but blocks the hypoalgesia. These results are interpreted as indicating that the initial effect of substance P is independent of any direct or indirect action mediated by opiate receptors. On the other hand, however, the antagonism of the hypoalgesia by naloxone suggests that this response is mediated via opiate receptors and, as substance P and opiates appear not to have any direct interaction at the cellular level, the endorphin-mediated hypoalgesia appears to be reflex in nature. Thus, the rebound overshoot of the response to substance P is visualized as an endorphin-mediated reflex activated by the increased transfer of nociceptive information provoked by substance P. The concept is proposed, therefore, that the transfer of nociceptive information is controlled by a servomechanism, or, in physiological terms, this transfer is under homeostatic control. Indeed, as naloxone itself reduces reaction time, it appears that an endogenous opioid is acting tonically to depress this transfer, at least under the conditions of the present experiments.

Animals↗
PubMedDate not supplied

Distribution of label after intrathecal administration of 125I-substance P in the rat.

Despite the widespread use of the intrathecal route for the administration of neuroactive agents, little is known about the penetration of these agents into the spinal cord. In the present study, 125I-substance P was injected via a spinal catheter to the thoracic or sacro-coccygeal spinal cord in the rat (350-400 g) anesthetized with urethane (2.5 g/kg). Spinal cords were removed rapidly at 1 or 10 min after injection and immediately frozen in CCl2F2. Frozen sections, 20 micron thick, were cut and mounted for autoradiography. Autoradiographs of transverse sections demonstrated that the label penetrated 700 to 1800 micron from the surface of the spinal cord at both levels. In longitudinal sections, this penetration extended about 0.5 cm rostrally and caudally from the site of injection. Serial autoradiographs of transverse sections showed a similar penetration rostro-caudally. In addition, venous blood samples were taken at 1, 6, 11 and 16 min after injection of the labelled peptide. Quantification of the radioactivity in the samples revealed that 0.8 to 3.5% of the total CPM injected had passed into the general circulation at these times. These data indicate that after intrathecal administration of radiolabelled substance P, the label penetrates into the grey matter of the spinal cord to presumed sites of action. They also suggest that the rostro-caudal extent of penetration is more localized than suggested from earlier studies which looked only at levels of radioactivity in pieces of whole spinal cord. Finally, our study has indicated that passage of label into the circulation is negligible at least for substance P.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗