Biomedical subjects

K Yashpal

Publications and source records attributed to K Yashpal.

At least 19 recordsLinked to original sources

PubMed2001

Knockdown of spinal metabotropic glutamate receptor 1 (mGluR(1)) alleviates pain and restores opioid efficacy after nerve injury in rats.

1. Nerve injury often produces long-lasting spontaneous pain, hyperalgesia and allodynia that are refractory to treatment, being only partially relieved by clinical analgesics, and often insensitive to morphine. With the aim of assessing its therapeutic potential, we examined the effect of antisense oligonucleotide knockdown of spinal metabotropic glutamate receptor 1 (mGluR(1)) in neuropathic rats. 2. We chronically infused rats intrathecally with either vehicle, or 50 microg day(-1) antisense or missense oligonucleotides beginning either 3 days prior to or 5 days after nerve injury. Cold, heat and mechanical sensitivity was assessed prior to any treatment and again every few days after nerve injury. 3. Here we show that knockdown of mGluR(1) significantly reduces cold hyperalgesia, heat hyperalgesia and mechanical allodynia in the ipsilateral (injured) hindpaw of neuropathic rats. 4. Moreover, we show that morphine analgesia is reduced in neuropathic rats, but not in sham-operated rats, and that knockdown of mGluR(1) restores the analgesic efficacy of morphine. 5. We also show that neuropathic rats are more sensitive to the excitatory effects of intrathecally injected N-methyl-D-aspartate (NMDA), and have elevated protein kinase C (PKC) activity in the spinal cord dorsal horn, two effects that are reversed by knockdown of mGluR(1). 6. These results suggest that activity at mGluR(1) contributes to neuropathic pain through interactions with spinal NMDA receptors and PKC, and that knockdown of mGluR(1) may be a useful therapy for neuropathic pain in humans, both to alleviate pain directly, and as an adjunct to opioid analgesic treatment.

Analgesics, Opioid↗

PubMed1999

Evidence for tonic activation of NK-1 receptors during the second phase of the formalin test in the Rat.

Behavioral, electrophysiological, and autoradiographic experiments were done to study the second nociceptive phase in the formalin test. In initial experiments, this second phase was attenuated by 1-10 mg of the NK-1 receptor antagonist CP-99,994, given subcutaneously 10, 30, or 60 min before formalin (n = 8-10) and by 20 microgram given intrathecally 20 min after formalin (n = 13); the inactive isomer CP-100,263 was ineffective. In electrophysiological experiments on single dorsal horn neurons in vivo, the excitatory responses to subcutaneous formalin injection (50 microliter, 2.5%) were attenuated by subsequent intravenously administration of the NK-1 receptor antagonist CP-96,345 (0.5 mg/kg; n = 8), given 35-40 min after formalin, but not by the inactive enantiomer CP-96,344 (0.5 mg/kg; n = 9). Finally, autoradiographic binding of exogenous [(125)I]BH-substance P in the lumbar cord was reduced at 5 and 25 min after formalin (50 microliter, 1 or 5%), with an intermediate level of reduction at 12 min. These data are interpreted as evidence that the second phase of nociceptive scores in the formalin test is attributable at least partially to tonic activation of NK-1 receptors at the spinal level, whether because of a temporally limited release of substance P, for example only during the first phase, but a slow removal or breakdown of substance P, or, more likely, because of tonic release from primary afferents throughout the second phase. Irrespective of the mechanism, it can be concluded that at least some of the persistent nociceptive effects associated with peripheral inflammation, or at least those provoked by subcutaneous injection of formalin, are mediated via continuous activation of NK-1 receptors at the level of the spinal dorsal horn; this may relate directly to mechanisms underlying prolonged nociceptive pains in humans.

Animals↗

PubMed1998

Influence of formalin concentration on the antinociceptive effects of anti-inflammatory drugs in the formalin test in rats: separate mechanisms underlying the nociceptive effects of low- and high-concentration formalin.

The present study has assessed the relationship between formalin-induced nociception and formalin-induced inflammation by comparing the dose-related effects of anti-inflammatory treatments on both nociceptive scores and plasma extravasation in the rat hind paw in response to high and low concentrations of formalin. The degree of plasma extravasation produced by 1% formalin did not differ significantly from that produced by the same volume of saline, and was not significantly affected by either of the anti-inflammatory agents. The 5% formalin injection produced significant plasma extravasation that was dose-dependently reduced by both dexamethasone and ibuprofen. The early-phase nociceptive responses to either 1 or 5% formalin were not affected significantly by either of the anti-inflammatory agents. In contrast, the late-phase nociceptive responses to 5%, but not 1%, formalin were dose-dependently reduced by both dexamethasone and ibuprofen. The present study suggests that there is a positive correlation between the nociceptive and inflammatory effects of formalin in the rat hind paw. However, only a high concentration of formalin, which produces significant plasma extravasation, is capable of demonstrating the antinociceptive effects of anti-inflammatory agents, and the effects are restricted to the late phase of the formalin test. Copyright 1998 European Federation of Chapters of the International Association for the Study of Pain.

Journal Article↗

PubMed1998

Comparison of the effects of treatment with intrathecal lidocaine given before and after formalin on both nociception and Fos expression in the spinal cord dorsal horn.

BACKGROUND: It has been proposed that the measure of noxious stimulus-induced Fos (the protein product of the immediate early gene c-fos) expression in the spinal cord dorsal horn of laboratory animals may provide an estimate of the potential of specific treatments to produce preemptive analgesia. The present study examined this hypothesis by comparing the effects of intrathecal lidocaine given before and after hindpaw formalin injection on persistent nociceptive responses and Fos expression in spinal cord dorsal horn of rats. METHODS: Formalin-induced nociception and Fos expression in the spinal cord, in response to a 50-microl injection of 2.5% formalin into the hind paw, were assessed in rats given an intrathecal injection of 50 microl 2% lidocaine by lumbar puncture between the L5 and L6 vertebrae, either 3 min before (pretreatment) or 5 min after (post-treatment) formalin injection. RESULTS: Pain behaviors (hindpaw licking, elevation, and favoring) in the second phase of the formalin test were significantly reduced by pretreatment, but were unaffected by post-treatment. The number of immunocytochemically stained Fos-positive cells and the immunoprecipitation of the Fos antibodies were reduced by pretreatment, and were also reduced, to a lesser extent, by post-treatment. CONCLUSIONS: The finding that persistent nociceptive behaviors and Fos expression were suppressed by intrathecal lidocaine pretreatment suggests that nociception in the second phase of the formalin test depends on increases in central hyperexcitability generated during the first phase. On the other hand, the finding that the intrathecal injection of lidocaine after formalin treatment reduced Fos expression but not nociceptive responses indicates an uncoupling of the behavioral and Fos protein responses to formalin and suggests that changes in Fos expression may not be a good predictor of the ability of agents to produce preemptive analgesia.

Anesthetics, Local↗

PubMed1997

Intense peripheral electrical stimulation evokes brief and persistent inhibition of the nociceptive tail withdrawal reflex in the rat.

In a study of modulation of nociception by sensory inputs, electrical stimulation was applied to specific sites in the hindlimb and effects on the nociceptive tail withdrawal reflex were monitored in the lightly anaesthetized rat. Stimulation was applied to previously defined sites in the hindlimb, meridian points femur-futu (ST-32), fengshi (GB-31) and zusanli (ST-36). It consisted of a 4 Hz train of 2 ms square pulses given for 20 min at 20 x the threshold intensity required for muscle twitch. Tail withdrawal was provoked by application of a noxious heat stimulus applied to the tip of the tail. Results were expressed as a percentage of the maximal possible inhibition which is achieved when the post-treatment latency is 2 x the pre-treatment latency otherwise known as the cut off. During stimulation, the latency of the withdrawal increased to approximately 70% of the maximal possible inhibition. Following stimulation, the inhibition persisted for > 1 h. Stimulation at 2 or 6 Hz elicited similar effects but stimulation at 8 Hz evoked inhibition during the stimulation only. Stimulation applied to sites away from defined meridian points inhibited tail withdrawal during the stimulation; no post-stimulation effect was produced. In acutely transected animals (< or = 48 h), stimulation of meridian points elicited a small, brief increase in latency but during stimulation only. At 7 and 14 days after spinal transection, this response during stimulation was greater in magnitude and a brief post-stimulation increase was also observed. The return of this latter effect was coincident with the return of bladder function. These data suggest that high intensity, low frequency electrical stimulation of hindlimb meridian points in the lightly anaesthetized rat produces both brief and persistent inhibitory effects on the nociceptive tail withdrawal reflex. These effects appear to be elicited by different mechanisms. The persistent effect may represent a plastic change in central inhibitory mechanisms. Data from spinal animals indicate a major participation of supraspinal structures but that spinal mechanisms are also capable of sustaining both types of effect.

Animals↗

PubMed1996

SR 48968 specifically depresses neurokinin A- vs. substance P-induced hyperalgesia in a nociceptive withdrawal reflex.

To determine the role of neurokinin A and tachykinin NK2 receptors in processing of nociceptive information at the spinal level, the selective NK2 receptor antagonist, SR 48968 (S)-N-methyl-N [4-(4-acetylamino-4-[phenyl piperidino)-2-(3,4-dichlorophenyl)-butyl] benzamide, was tested for its effects on the hyperalgesia produced in the tail flick reflex by intrathecal administration of neurokinin A and of substance P. SR 48968 was also tested in a model in which noxious peripheral stimulation has been shown to produce hyperalgesia via a substance P mechanism. SR 48968 given intrathecally had a dose-dependent inhibitory effect on both the behaviour and the hyperalgesia induced by neurokinin A but not on either of these effects produced by substance P. In addition, systemic administration of SR 48968 depressed the hyperalgesic effect of intrathecal administration of neurokinin A. First, this evidence indicates a unique role for neurokinin A in the spinal cord as distinct from that of its homologue, substance P. and confirms that neurokinin A acts via the tachykinin NK2 receptor, rather than non-specifically via the NK1 receptor. Second, the data indicate that in this model substance P does not express any of its effects non-selectively via activation of NK2 receptors. Third, SR 48968 appears to have access to the spinal cord upon systemic administration. Fourth, intrathecal administration of the NK1 receptor antagonist, CP-96,345 [(2S,3S)-cis-2-(diphenylmethyl)-N-[(2-methoxy-phenyl)-methyl]-1- azabicyclo [2.2.2]-octan-3-amine], had no effect on the responses to intrathecal administration of neurokinin A. Finally, the hyperalgesia produced by sustained noxious thermal stimulation of the tip of the tail was unaffected by intrathecal administration of SR 48968; thus, it remains to find a physiological response in which endogenous neurokinin A and NK2 receptors at the spinal level are involved in the rat in vivo.

Animals↗

PubMed1996

Effects of preemptive or postinjury intrathecal local anesthesia on persistent nociceptive responses in rats. Confounding influences of peripheral inflammation and the general anesthetic regimen.

BACKGROUND: Although experimental evidence indicates that preemptive intrathecal treatment with local anesthetics reduces postinjury neuronal hyperexcitability, clinical evidence indicates that preemptive treatments do not consistently reduce postoperative pain. The current study used experimental models of postinjury nociception, in which rats received subcutaneous or intraarticular injections of the irritant formalin, to evaluate the effects of peripheral inflammation, or the use of agents supplemental to anesthesia, as possible confounding influences on the effectiveness of preinjury and postinjury intrathecal local anesthetic treatments. METHODS: In experiment 1, lumbar intrathecal lidocaine (30 microliters, 2%), given either 5 min before or 5 min after hind paw injection of 50 microliters of varying concentrations of formalin, was compared with intrathecal cerebrospinal fluid, for their effects on nociceptive responses in the late phase of the formalin test. Furthermore, the effect of hind paw injection of 50 microliters of 2.5, 3.75, or 5.0% formalin on peripheral inflammation was assessed by measuring plasma extravasation in the hind paws of rats given Evans Blue dye (50 mg/kg, intravenous). In experiment 2, rats received a deep tissue injury (100 microliters of 5.0% formalin into the knee joint) while under halothane anesthesia. In addition to halothane (3-4%), rats received either saline, pentobarbital (13 mg/kg, intraperitoneal), or pentobarbital + morphine (0.5 mg/kg, intravenous), with or without preinjury or postinjury spinal anesthesia using intrathecal bupivacaine (30 microliters, 0.75%), to assess the effects of supplemental treatments on the preemptive effects of intrathecal bupivacaine. RESULTS: Lumbar intrathecal lidocaine pretreatment, but not posttreatment, significantly reduced late phase nociceptive responses to hind paw injections of 2.5% formalin. The preemptive effects of lidocaine were overridden in rats that received hind paw injections of 3.75 and 5.0% formalin. Hind paw injection of 50 microliters of 3.75 or 5.0%, but not 2.5% formalin produced an increase in plasma extravasation. Either pentobarbital or pentobarbital + morphine treatment, or a pentobarbital + morphine treatment and postinjury treatment with intrathecal bupivacaine failed to produce a significant reduction in the nociceptive response to the deep tissue injury. However, rats that received pentobarbital + morphine treatments and intrathecal bupivacaine before the injury had significantly reduced nociceptive responses to deep tissue injury when compared to the saline control group, but not to the group that received pentobarbital + morphine treatment and postinjury treatment with bupivacaine. CONCLUSIONS: The current results attest to the important effects of ongoing inputs from inflamed tissue, and the use of supplemental treatments, as important confounding factors that may influence the effectiveness of preemptive spinal anesthesia for postoperative pain.

Analgesia↗

PubMed1995

Implication of a nitric oxide synthase mechanism in the action of substance P: L-NAME blocks thermal hyperalgesia induced by endogenous and exogenous substance P in the rat.

The effects of i.p. administration of the nitric oxide synthase inhibitor NG-nitro-L-arginine methylester (L-NAME) and its inactive isomer, D-NAME, were tested in two nociceptive paradigms in the rat. In the first paradigm, rats were lightly anaesthetized with a mixture of chloral hydrate (120 mg/kg, i.p.) and sodium pentobarbital (20 mg/kg, i.p.). Tail flick reaction times were monitored and thermal hyperalgesia was induced by immersion of the tail in hot water at 55 degrees C for 1.5 min. In the groups of rats pretreated with saline (n = 5), 100 mg/kg D-NAME (n = 6), 10 (n = 5) or 25 (n = 6) mg/kg L-NAME, this thermal injury induced a transient reduction in the reaction time that was 54-59% of the baseline value. However, in the groups of rats pretreated with 50 (n = 6) or 100 (n = 7) mg/kg L-NAME the reaction times were 73.9 +/- 2.7% (P < 0.05) and 102.3 +/- 0.9% (P < 0.001) of the baseline values respectively, indicating a block of the hyperalgesic responses seen in the other groups. As this hyperalgesia has been reported to be blocked by NK-1 receptor antagonists, it is suggested that it is due to the action of endogenous substance P. In the second paradigm, tail flick responses were monitored in the awake rat and thermal hyperalgesia was induced by intrathecal administration of substance P (6.5 nmol) via a chronically implanted catheter.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1995

Noxious peripheral stimulation produces antinociception mediated via substance P and opioid mechanisms in the rat tail-flick test.

Physiological experiments were run to examine the effects of noxious thermal stimulation of one hindpaw on the tail-flick reflex in the lightly anesthetized rat. Male Sprague-Dawley rats were anesthetized with an i.p. injection of a mixture of Na-pentobarbital (20 mg/kg) and chloral hydrate (120 mg/kg). After baseline readings were taken in the tail-flick test, either a non-noxious or a noxious stimulus was applied which consisted of immersion of one hindpaw in water at 40, 45, 50 or 55 degrees C for 1.5 min. After immersion, tail-flick readings were taken at 3-min intervals for at least 16 min. Paw immersion in water at 55 degrees C induced an antinociceptive response, consisting of an increase in the reaction time, at 0.5 min after immersion. Recovery to baseline levels occurred over the next 3-6 min. Immersion at lower temperatures provoked smaller antinociceptive responses, except at 40 degrees C, where readings remained around the baseline values. The increase in reaction time in response to immersion at 55 degrees C was attenuated or blocked by the novel, nonpeptide substance P (NK-1) receptor antagonist, CP-96,345, administered s.c. 30 or 60 min, respectively, prior to paw immersion. Similar injection of CP-96,344, the inactive stereoisomer, had no effect on the response, while another NK-1 receptor antagonist, CP-99,994, also attenuated the antinociceptive effect of the immersion. The increase in reaction time induced by immersion at 55 degrees C was absent in animals treated neonatally with capsaicin.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1995

Mechanisms underlying antinociception provoked by heterosegmental noxious stimulation in the rat tail-flick test.

Physiological studies were conducted to examine the effects of noxious stimulation of one hindpaw or one forepaw on the latency of the withdrawal reflex in the tail-flick test in lightly anesthetized spinally intact or transected rats. Male Sprague-Dawley rats were anesthetized with an intraperitoneal injection of a mixture of Na-pentobarbital (20 mg/kg) and chloral hydrate (120 mg/kg). After baseline readings were taken in the tail-flick test, the effects of various noxious stimuli applied to remote body regions were assessed. The noxious stimuli included unilateral or bilateral hindpaw or unilateral forepaw thermal (immersion in water at 55 degrees C for 90 s), unilateral or bilateral chemical (subcutaneous hindpaw injection of 50 microliters of 5% formalin) and unilateral or bilateral mechanical (pinch with clamp exerting a force of 14.75 or 27 N) stimulation. Bilateral chemical and thermal, and unilateral thermal stimulation induced an antinociceptive response, consisting of an increase in tail-flick latency, peaking at 30 s after stimulation. Recovery to baseline levels occurred over the next 3-6 min. The antinociceptive effect of noxious thermal stimulation was attenuated or absent in chronically spinalized animals (T6/7) following hindpaw or forepaw immersion, respectively. Noxious mechanical stimulation had no effect on tail-flick latency. The data provide evidence that a noxious thermal or chemical stimulus produces a heterosegmental antinociceptive effect which is mediated in part via a supraspinal mechanism and in part via a local spinal mechanism.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1995

Noxious thermal and chemical stimulation induce increases in 3H-phorbol 12,13-dibutyrate binding in spinal cord dorsal horn as well as persistent pain and hyperalgesia, which is reduced by inhibition of protein kinase C.

We have previously suggested that protein kinase C (PKC) contributes to persistent pain in the formalin test. This study compared the effects of pharmacological inhibition of PKC with either GF 109203X or chelerythrine on persistent pain following noxious chemical stimulation with its effects on mechanical hyperalgesia, which develops in the hindpaw contralateral to an injury produced by noxious thermal stimulation. Furthermore, we have assessed changes in membrane-associated PKC in spinal cord in response to both noxious chemical and thermal stimulation. Nociceptive responses, to a hindpaw injection of 50 microliters of 2.5% formalin, and flexion reflex thresholds, to mechanical stimulation (Randall-Selitto test) in the hindpaw contralateral to a thermal injury (15 sec immersion in water at 55 degrees C), were assessed following intrathecal injection of PKC inhibitors (GF 109203X or chelerythrine). Changes in the levels of membrane-associated PKC, as assayed by quantitative autoradiography of the specific binding of 3H-phorbol-12,13-dibutyrate (3H-PDBu) in spinal cord sections, were assessed in rats after noxious chemical (50 microliters of 5.0% formalin) and noxious thermal (90 sec immersion in water at 55 degrees C) stimulation. Inhibitors of PKC (GF 109203X, chelerythrine), produced significant reductions of nociceptive responses to 2.5% formalin, as well as a significant reduction in the mechanical hyperalgesia in the hindpaw contralateral to a thermal injury. In addition, both noxious chemical and thermal stimulation produced significant increases in specific 3H-PDBu binding in the dorsal horn of the lumbar spinal cord, likely reflecting alterations in membrane-associated PKC. The results provide both pharmacological and anatomical evidence that persistent pain produced by chemical stimulation with formalin and mechanical hyperalgesia in the hindpaw contralateral to a thermal injury are influenced by the translocation and activation of PKC in spinal cord dorsal horn neurons.

Alkaloids↗

PubMed1995

mu-, delta- and kappa-opiate receptors mediate antinociception in the rat tail flick test following noxious thermal stimulation of one hindpaw.

Experiments were performed to investigate the possible involvement of spinal mu-, delta- and kappa-opiate receptors in mediating the antinociceptive effects of noxious thermal stimulation of one hindpaw on the tail flick reflex in the rat. Male Sprague-Dawley rats were implanted with chronic intrathecal catheters to the lumbar level of the spinal cord. After 5 to 7 days, they were lightly anesthetized with an i.p. injection of a mixture of Na-pentobarbital (20 mg/kg) and chloral hydrate (120 mg/kg). After baseline readings were taken in the tail flick test a conditioning noxious thermal stimulus, which consisted of immersion of one hindpaw in water at 55 degrees C for 90 sec, was applied and the effects on the latency of the tail withdrawal reflex were studied over the next 30 min. In animals pretreated with CSF intrathecally 10 min before the stimulus, an increase in tail flick reaction time was observed peaking at 30 sec after the stimulus. This response was attenuated in a dose-related manner by preadministration of the specific mu-opiate receptor antagonist, beta-funaltrexamine, the specific delta-opiate receptor antagonist, H-Tyr-Tic psi[CH2NH]-Phé-Phe-OH or the specific kappa-opiate receptor antagonist, nor-binaltorphimine. The data show that the antinociceptive effect on the tail withdrawal reflex from a brief noxious thermal stimulus is provoked heterosegmentally by the noxious conditioning stimulus to the hindpaw and is mediated by the endogenous release of ligands that bind to mu-, delta- and kappa-opiate receptors in the spinal cord.

Analgesics↗

PubMed1994

Noxious stimulation decreases substance P binding in rat spinal dorsal horn: competition by endogenous ligand?

To determine the participation of NK-1 receptors in mediating inputs from noxious thermal stimulation, sustained noxious stimulation was applied to anaesthetized rats by immersing one hind paw in water for 1.5 min at different temperatures. After sacrificing the animal, lumbar spinal cords were removed and 20 microns sections were incubated with [125I]BH-substance P. Compared with unstimulated controls, binding was the least in rats given a 55 degrees C stimulus and sacrificed 1 min after the stimulus; the greatest reduction was found in the superficial dorsal horn. Rats sacrificed at 10 min showed intermediate binding levels. Groups given less intense stimuli showed smaller decreases in binding. It is suggested that the decrease in binding was due to occupation of receptors by endogenous ligand, which is consistent with the idea that noxious stimulation evokes the release of substance P at the spinal level.

Animals↗

PubMed1994

Intracellular messengers contributing to persistent nociception and hyperalgesia induced by L-glutamate and substance P in the rat formalin pain model.

The contribution of the intracellular messengers nitric oxide, arachidonic acid and protein kinase C to persistent nociception in response to tissue injury in rats was examined following the subcutaneous injection of formalin into the hindpaw. Formalin injury-induced nociceptive behaviours were reduced by intrathecal pretreatment with inhibitors of nitric oxide synthase (NG-nitro-L-arginine methyl ester, L-NAME), arachidonic acid (dexamethasone) or protein kinase C [protein kinase C (19-26) and 1-95-(isoquinolinesulphonyl)-2-methylpiperazine dihydrochloride, H-7]. Each of these agents affected the tonic, but not the acute, phase of the formalin response. Furthermore, none of these agents affected mechanical or thermal flexion reflex thresholds in rats not injected with formalin. Conversely, formalin-induced nociceptive responses were enhanced by stimulators of nitric oxide (sodium nitroprusside), arachidonic acid metabolism (arachidonic acid) or protein kinase C [(+/-)-1-oleoyl-2-acetyl-glycerol], and were slightly reduced by inositol trisphosphate. Mechanical flexion reflexes were also reduced by arachidonic acid, while thermal flexion reflexes were reduced after treatment with sodium nitroprusside, arachidonic acid or [(+/-)-1-oleoyl-2-acetyl-glycerol]. The enhancement of formalin nociceptive behaviours (hyperalgesia) in rats treated with L-glutamate or substance P was reversed by pretreatment with inhibitors of nitric oxide (L-NAME), arachidonic acid (dexamethasone) or protein kinase C (H-7). The results suggest that central sensitization and persistent nociception following formalin-induced tissue injury, and the hyperalgesia in the formalin test induced by L-glutamate and substance P, are dependent on the intracellular messengers nitric oxide, arachidonic acid and protein kinase C.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗

PubMed1994

Specific contribution of lumbar spinal mechanisms to persistent nociceptive responses in the formalin test.

To determine whether a lumbar spinal mechanism mediates the late phase of the nociceptive response in the formalin test, we compared the effects of intrathecal (i.t.) lidocaine given pre- or post-formalin at the lumbar or thoracic level. Pre- but not post-formalin administration of lidocaine to the lumbar level significantly attenuated late phase nociceptive responses. In contrast, neither pre- nor post-formalin administration of lidocaine to the mid-thoracic level altered nociceptive responses. In rats chronically spinalized at the mid-thoracic level, nociceptive responses to formalin were observed which were blocked by i.t. pre-treatment with lidocaine at the lumbar level. These results suggest that a specific lumbar spinal mechanism is involved in the initiation of persistent nociception in the formalin test.

Anesthesia, Spinal↗

PubMed1993

Neural mediation of the cardiovascular responses to intrathecal administration of substance P in the rat: slowing of the cardioacceleration by an adrenal opioid factor.

Substance P, given intrathecally at the second (T2) or ninth (T9) thoracic level in the anesthetized rat, increased heart rate, arterial pressure and circulating catecholamines. At T9 in adrenalectomized animals and at T2 in intact animals, the cardioacceleration was more abrupt than in intact animals injected at T9 suggesting that the adrenals are not necessary for the cardiovascular responses and that the adrenals may have released a factor which slows the neurally mediated cardioacceleration. As opioids are co-released with catecholamines from the adrenals, naloxone (10 mg/kg i.v.) or nalorphine HCl (which does not cross the blood-brain barrier; 10 mg/kg s.c.) was given 5 min before administration of substance P at T9 in intact rats. In both groups the cardioacceleration was similar to that elicited in adrenalectomized animals, indicating that the adrenal factor was opioid and that its action was peripheral rather than central. When propranolol (10 mg/kg i.v.) was given 3 or 15 min before, substance P increased arterial pressure but heart rate was unchanged, indicating that the opioid factor was not slowing the cardioacceleration by a direct effect on the heart. The results indicate that intrathecal administration of substance P produces a neurally mediated increase in arterial pressure and heart rate and induces the release of an adrenal opioid factor which slows the neurally-mediated cardioacceleration by an action in the periphery. This indicates a functional interaction between humoral and neural sympathetic mechanisms regulating the cardiovascular system.

Adrenal Glands↗

PubMed1993

CP-96,345, but not its stereoisomer, CP-96,344, blocks the nociceptive responses to intrathecally administered substance P and to noxious thermal and chemical stimuli in the rat.

The effects of subcutaneous administration of the non-peptide NK-1 (substance P) receptor antagonist, CP-96,345, and its stereoisomer, CP-96,344, were tested in three nociceptive paradigms in the rat. In the first paradigm, tail flick responses were monitored before and after intrathecal administration of substance P (6.5 nmol) in rats pretreated subcutaneously with saline, CP-96,344 (5 mg/kg) or CP-96,345 (5 mg/kg). In the control groups, pretreated with saline (n = 6) or with CP-96,344 (n = 5), substance P reduced the tail flick reaction time at 1 min after administration to 38.3 +/- 5.1 (mean +/- S.E.M.) and 32.1 +/- 7.7% of the mean baseline value, respectively. In contrast, in the group pretreated with CP-96,345 (n = 6) the reaction time following administration of substance P was 98.8 +/- 3.3% of the baseline reaction time; this value was not significantly different from the baseline value of this group, indicating a block (P < 0.01) of the substance P-induced facilitation of the tail flick response. In the second paradigm, rats were anesthetized with a mixture of chloral hydrate (120 mg/kg, i.p.) and sodium pentobarbital (20 mg/kg, i.p.), and the effects were determined on tail flick reaction time of a sustained noxious cutaneous stimulation, immersing the tip of the tail in hot water at 55 degrees C. In the groups of rats pretreated with saline (n = 4) or with CP-96,344 (n = 7), this noxious stimulus produced a transient decrease in reaction time to 62-74% of the baseline value.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

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↗