Biomedical subjects

K M Zhang

Publications and source records attributed to K M Zhang.

At least 19 recordsLinked to original sources

PubMed2001

Orphanin FQ produces gender-specific modulation of trigeminal nociception: behavioral and electrophysiological observations.

The present study aimed to determine if orphanin FQ, an endogenous ligand for the opioid receptor like-1 receptor, produces gender-specific effects in the modulation of N-methyl-D-aspartate (NMDA)-evoked responses of trigeminal nociceptive neurons, and in the NMDA-induced nociceptive behavior. Single-unit extracellular recordings were made from nociceptive-specific and wide dynamic range neurons in the superficial and deeper dorsal horn of the medulla (trigeminal nucleus caudalis) in anesthetized (1.5 g/kg urethane) rats. In the proestrous female, orphanin FQ applied microiontophoretically produced facilitation of the NMDA-evoked responses in 50% (16/32) of nociceptive neurons, inhibition in 31% (10/32), and biphasic effects in 19% (6/32). In contrast, in the male, it inhibited the responses in 86% (18/21), and facilitated the responses in 14% (4/21). In ovariectomized animals, orphanin FQ inhibited the responses in 75% (9/12) of nociceptive neurons, facilitated the responses in 17% (2/12) and produced biphasic effects in 8% (1/12). In contrast, in estradiol-treated ovariectomized rats, it facilitated the responses in 46% (5/11), inhibited the responses in 36% (4/11) and produced biphasic effects in 18% (2/11). For behavioral studies, NMDA-induced scratching behavior was used to assess the effects of orphanin FQ. Twenty-eight male, ovariectomized and estradiol-treated ovariectomized rats were microinjected with NMDA (2 nmol in 10 microl) alone through a cannula implanted in the medullary region, while another 27 rats were microinjected with orphanin FQ (10 nmol in 10 microl) 10 min prior to giving NMDA. Orphanin FQ reduced the NMDA-induced nociceptive scratching behavior by 92% in the male, and by 96% in ovariectomized rats. In contrast, in estradiol-treated ovariectomized animals, orphanin FQ facilitated the NMDA-induced scratching behavior by 210%. We conclude from these studies that orphanin FQ is primarily pronociceptive in the female and primarily antinociceptive in the male. Furthermore, we suggest that estrogen is involved in generating the gender-specific effects of orphanin FQ.

Action Potentials↗

PubMed2000

Endomorphin-1 and endomorphin-2 modulate responses of trigeminal neurons evoked by N-methyl-D-aspartic acid and somatosensory stimuli.

The present study investigated the modulation of N-methyl-D-aspartate (NMDA)-evoked and peripheral cutaneous stimulus-evoked responses of trigeminal neurons by endomorphins, endogenous ligands for the mu-opioid receptor. Effects of endomorphins, administered microiontophoretically, were tested on the responses of nociceptive neurons recorded in the superficial and deeper dorsal horn of the medulla (trigeminal nucleus caudalis) in anesthetized rats. Endomorphin-1 and endomorphin-2 predominantly reduced the NMDA-evoked responses, producing an inhibitory effect of 54.1 +/- 2.96% (mean +/- SE; n = 34, P < 0.001) in 92% (34/37) of neurons and 63.6 +/- 3.61% (n = 32, P < 0.001) in 91% (32/35) of neurons, respectively. The inhibitory effect of endomorphins was modality specific; noxious stimulus-evoked responses were reduced more than nonnoxious stimulus-evoked responses. Naloxone applied at iontophoretic current that blocked the inhibitory effect of [D-Ala(2), N-Me-Phe(4), Gly(5)-ol]-enkephalin, reduced the peak inhibitory effect of endomorphins on the NMDA- and natural stimulus-evoked responses. We suggest that endomorphins by acting at micro-opioid receptor selectively modulate noxious stimulus-evoked responses in the medullary dorsal horn.

Analgesics, Opioid↗

PubMed1999

Salbutamol and the conditioning of latissimus dorsi for cardiomyoplasty.

BACKGROUND: Cardiomyoplasty is a new surgical alternative therapy for CHF. Although conditioning of muscle for cardiomyoplasty has a positive effect on fatigue resistance it also produces negative effects. In this study we assessed the effect of salbutamol, a beta2-agonist, on both the positive and the negative effects of conditioning. METHODS: In a control group of six animals one latissimus dorsi was subject to chronic, 1 Hz, low-frequency stimulation (CLFS) while the other served as a control. The experimental group of seven dogs received a continuous SC infusion of salbutamol and one latissimus dorsi was subjected to CLFS. The other muscle demonstrated the effects of salbutamol per se. After 42 days the animals were anesthetized and fatigue resistance, muscle mass, and mechanical properties of the muscles were evaluated. RESULTS: Salbutamol increased muscle mass, tetanic tension, and rate of rise and fall of tetanic tension. It diminished fatigue resistance and had no effect on shortening velocity. Chronic stimulation decreased muscle mass, tetanic tension, rate of rise and fall of tetanic tension, and muscle shortening velocity in both groups of dogs. Salbutamol diminished the declines in muscle mass, rate of tension development, and rate of muscle shortening due to CLFS, but did not change the effects of CLFS on tetanic tension and the rate of fall of tetanic tension. Salbutamol did not alter the increase in fatigue resistance induced by CLFS. CONCLUSIONS: The favorable effect of CLFS on fatigue resistance was unaffected by salbutamol. The unfavorable effects of CLFS on loss of muscle mass, rate of tension development, and decline in shortening velocity were partially blocked by salbutamol, improving the ability of the latissimus dorsi to augment cardiac systole.

Albuterol↗

PubMed1999

Orphanin FQ (nociceptin) modulates responses of trigeminal neurons evoked by excitatory amino acids and somatosensory stimuli, and blocks the substance P-induced facilitation of N-methyl-D-aspartate-evoked responses.

The present investigation details the modulation of medullary dorsal horn neuron responses to excitatory amino acids and peripheral cutaneous stimuli by orphanin FQ (nociceptin), an endogenous ligand for the opioid receptor-like, receptor. Effects of orphanin FQ, administered microiontophoretically or given intracerebroventricularly, were tested on the responses of nociceptive-specific, wide dynamic range and low threshold neurons recorded in the superficial and deeper dorsal horn of the medulla (trigeminal nucleus caudalis) in anesthetized (urethane or pentobarbital) male rats. Microiontophoretic application of orphanin FQ reduced the N-methyl-D-aspartate-evoked responses in 86% (71/82) of neurons, and the (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid-evoked responses in 86% (30/35) of neurons. However, orphanin FQ produced a longer lasting inhibitory effect on the N-methyl-D-aspartate-evoked responses relative to the (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid-evoked responses. The inhibitory effect of orphanin FQ was not modality-specific, responses evoked by noxious as well as non-noxious stimuli were reduced in 22/23 neurons. However, the inhibitory effect was more pronounced on noxious stimulus-evoked responses. Naloxone applied at currents that antagonized the inhibitory effects of selective agonists at mu and kappa opioid receptors failed to inhibit the effects of orphanin FQ. Microiontophoretic co-application of substance P with N-methyl-D-aspartate facilitated the N-methyl-D-aspartate-evoked responses in 52% (26/50) of nociceptive neurons. Orphanin FQ blocked or reduced the substance P-induced facilitation by 86+/-24.4% (n = 14). In order to compare electrophysiological data with previous behavioral observations, effects of orphanin FQ administered intracerebroventricularly were tested on the excitatory amino acid-evoked responses. Orphanin FQ reduced the N-methyl-D-aspartate-evoked responses in 85% (11/13) of neurons whereas the (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid-evoked responses were facilitated in 69% (9/13) of neurons. We suggest that orphanin FQ produces a predominantly inhibitory effect on, (i) noxious stimuli evoked responses, (ii) excitatory amino acid receptor-mediated transmission and, (iii) the substance P-induced facilitation of the N-methyl-D-aspartate-evoked responses. We conclude that orphanin FQ primarily produced an antinociceptive action at the level of the dorsal horn of the medulla.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗

PubMed1998

Transcription rates of SERCA and phospholamban genes change in response to chronic stimulation of skeletal muscle.

Chronic low frequency stimulation of predominantly fast-twitch skeletal muscles decrease the levels of SERCA1 (fast-twitch sarco(endo)plasmic reticulum Ca2+-ATPase) mRNA, and increase the levels of SERCA2 (slow-twitch sarco(endo)plasmic reticulum Ca2+-ATPase) and phospholamban mRNAs. To assess the role of transcription in these changes in mRNA levels, nuclei were isolated from chronically stimulated canine latissimus dorsi muscles and transcription rates were estimated by nuclear run-on assays. Decreases in the rates of SERCA1 gene transcription matched the fall in its mRNA level and increases in the rates of SERCA2 and phospholamban gene transcription matched the increases in their mRNAs.

Animals↗

PubMed1998

The beta2-agonist salbutamol affects the expression of phospholamban and both isoforms of SERCA in canine skeletal muscle and blocks changes in these induced by neuromuscular stimulation.

Chronic administration of salbutamol induced expression of hybrid fibers in canine skeletal muscles. Fast-twitch fibers expressed SERCA2a (the slow-twitch isoform of sarcoplasmic reticulum Ca2+-ATPase) and slow-twitch fibers expressed SERCA1 (the fast-twitch isoform of the Ca2+-ATPase). The proportion of fibers that became hybrid increased from a small percentage in the control muscles to 30% in the predominantly fast-twitch latissimus dorsi and to 45% in the predominantly slow-twitch vastus intermedius. In contrast to this response by the SERCA genes the phospholamban gene response was muscle specific. The fraction of fibers that expressed phospholamban decreased slightly in the latissimus dorsi while increasing moderately in the vastus intermedius. The effects of chronic neurostimulation of the latissimus dorsi on SERCA1, SERCA2a and phospholamban levels were mostly blocked by salbutamol. While 100% of fibers from neurostimulated muscles expressed phospholamban, only 51% of the fibers from the neurostimulated and salbutamol-treated muscles expressed it. In the neurostimulated muscle, very few muscle fibers expressed SERCA1a while 61% of the fibers that received salbutamol expressed it, albeit as hybrid fibers. The levels of SERCA2a in response to these interventions were just the opposite. In the neurostimulated muscle 37.5% of fibers were hybrid and 62.5% expressed SERCA2a only. With co-administration of neurostimulation and salbutamol, 61.3% of fibers were hybrid and 38.7% expressed SERCA2a only.

Adrenergic alpha-2 Receptor Agonists↗

PubMed1998

alpha2-adrenoceptors modulate NMDA-evoked responses of neurons in superficial and deeper dorsal horn of the medulla.

Extracellular single unit recordings were made from neurons in the superficial and deeper dorsal horn of the medulla (trigeminal nucleus caudalis) in 21 male rats anesthetized with urethan. NMDA produced an antagonist-reversible excitation of 46 nociceptive as well as nonnociceptive neurons. Microiontophoretic application of a preferential alpha2-adrenoceptor (alpha2AR) agonist, (2-[2, 6-dichloroaniline]-2-imidazoline) hydrochloride (clonidine), reduced the NMDA-evoked responses of 86% (6/7) of nociceptive-specific (NS) neurons, 82% (9/11) of wide dynamic range (WDR) neurons, and 67% (4/6) of low-threshold (LT) neurons in the superficial dorsal horn. In the deeper dorsal horn, clonidine inhibited the NMDA-evoked responses of 94% (16/17) of NS and WDR neurons and 60% (3/5) of LT neurons. Clonidine facilitated the NMDA-evoked responses in 14% (1/17) of NS, 9% (1/11) of WDR, and 33% (2/6) of LT neurons in the superficial dorsal horn. Idazoxan, an alpha2AR antagonist, reversed the inhibitory effect of clonidine in 90% (9/10) of neurons, whereas prazosin, an alpha1-adrenoceptor antagonist with affinity for alpha2BAR, and alpha2CAR, were ineffective. We suggest that activation of alpha2ARs produces a predominantly inhibitory modulation of the NMDA-evoked responses of nociceptive neurons in the medullary dorsal horn.

Adrenergic alpha-Agonists↗

PubMed1997

Fast- and slow-twitch isoforms (SERCA1 and SERCA2a) of sarcoplasmic reticulum Ca-ATPase are expressed simultaneously in chronically stimulated muscle fibers.

Using an immunohistochemical double-labeling technique, we observed that different isoforms of sarcoplasmic reticulum Ca-ATPase are co-expressed in single fibers of canine fast-twitch skeletal muscles stimulated chronically at low frequency. By 7 days of neuromuscular stimulation, the population of hybrid fibers expressing both SERCA1 and SERCA2a [fast- and slow-twitch isoforms of sarco(endo)plasmic reticulum Ca(2+)-ATPase] had increased from 1.5% to 9.2% of fibers. By 14 days of stimulation 90% of the pure fast-twitch fibers (expressing only SERCA1) were replaced by hybrid fibers. An additional 28 days of stimulation caused all fast-twitch fibers to express SERCA2a at the same level as found in nonstimulated slow-twitch fibers (expressing only SERCA2a). At this time, one-half of the previously hybrid fibers had become pure-slow-twitch fibers. The remaining one-half of the hybrid fibers expressed SERCA1 at a very low level. Extending stimulation to 70 days did not further change the percentage of fibers that were slow-twitch or hybrid. Immunoblot studies at the whole-muscle level confirmed that changes in SERCA expression at 42 days of neuromuscular stimulation were complete. Immunohistochemical analysis of longitudinal sections of muscle showed that the changes in SERCA protein were uniform along the length of the muscle fiber, indicating that nuclei along its length responded equally to chronic stimulation.

Animals↗

PubMed1997

Correlations between MyoD, myogenin, SERCA1, SERCA2 and phospholamban transcripts during transformation of type-II to type-I skeletal muscle fibers.

Canine latissimus dorsi, composed predominantly of fast-twitch muscle fibers, were subjected to chronic 1 Hz neuromuscular stimulation for periods up to 42 days to induce changes in gene expression. This produced down regulation of SERCA1 (fast-twitch isoform of sarco(endo)plasmic reticulum Ca2+-ATPase), a gene product of fast-twitch muscle, and up regulation fo SERCA2 (slow-twitch isoform of sarco(endo)plasmic reticulum Ca2+-ATPase) and phospholamban, products of genes expressed by slow-twitch muscles. To assess the involvement of MyoD and myogenin in the regulation of the expression of these genes their levels were measured during the stimulation period. The prompt, at 7 days, fall in SERCA1 mRNA preceded the fall in MyoD by about 7 days, suggesting that the decline in MyoD was not causally related to the decline in SERCA1. The prompt rise in SERCA2 mRNA at 7 days preceded the rise in myogenin by 14 days. The rise in myogenin at 21 days did correlate with the similar rise in phospholamban mRNA.

Animals↗

PubMed1997

Induction of molecular and mechanical transformations in canine skeletal muscle by chronic neuromuscular stimulation.

The canine latissimus dorsi was stimulated at 1 Hz via the thoracodorsal nerve for 70 days. Seven days of muscle stimulation caused muscle mass, fibre cross-sectional areas, and tetanic tensions to decrease. Fourteen days of stimulation produced marked decreases in Ca(2+)-uptake rates in a membrane fraction containing sarcoplasmic reticulum. At this time there was a decline in fusion frequency, but no statistically significant changes in time-to-peak tension, total contraction times, or half-relaxation times. With 42 days of stimulation a switch from the fast-twitch to the slow-twitch phenotype was indicated by elevations in the levels of expression of the slow-twitch isoforms of sarco(endo)plasmic reticulum Ca(2+)-ATPase and myosin heavy chain-I, and increases in half-relaxation times, total contraction times and time-to-peak tensions. Decreases in muscle shortening velocity correlated negatively with increases in myosin heavy chain-I levels. Up-regulation of the slow-twitch isoforms of sarco(endo)plasmic reticulum Ca(2+)-ATPase increases in half-relaxation times. The changes in the slow-twitch isoform of sarco(endo)plasmic reticulum Ca(2+)-ATPase and myosin heavy chain-I levels indicated coordinate expression of these two proteins in chronically stimulated muscles.

Animals↗

PubMed1996

Role of opioid receptors (mu, delta 1, delta 2) in modulating responses of nociceptive neurons in the superficial and deeper dorsal horn of the medulla (trigeminal nucleus caudalis) in the rat.

This report describes the effects of intravenously administered agonists and antagonists at mu-, delta 1- and delta 2-opioid receptors on the A delta- and C-fiber-evoked responses of trigeminal nociceptive neurons in anesthetized rats. Extracellular single unit recordings were made from 61 nociceptive neurons (23 NS, 38 WDR) in the superficial and 37 nociceptive neurons (3 NS, 34 WDR) in the deeper dorsal horn of the medulla (trigeminal nucleus caudalis). Administration of either the delta 1-receptor agonist [D-Pen2,5]enkephalin (DPDPE; 0.05-2 mg/kg), the delta 2-receptor agonist [D-Ala2, Glu4]deltorphin (DELT; 1-2 mg/kg) or the mu-receptor agonist [D-Ala2, N-MePhe4, Gly5-ol]enkephalin (DAMGO; 0.05-1 mg/kg) inhibited the A delta- and C-fiber-evoked responses of nociceptive neurons in the superficial and deeper dorsal horn. The inhibitory effect was more pronounced on the C-fiber-evoked responses than on the A delta-fiber-evoked responses. In other neurons, DPDPE also produced facilitation, or inhibition followed by facilitation, or differential effects (inhibition of the C-fiber-evoked responses and facilitation of the A delta-fiber-evoked responses) on the A delta- and C-fiber-evoked responses. The effects of DPDPE were antagonized by 7-benzylidenenaltrexone (BNTX, 0.4-1 mg/kg), a delta 1-receptor antagonist, in 88% (7/8) of neurons. Naltriben (NTB, 0.7-1 mg/kg), a delta 2-receptor antagonist, antagonized the effect of both DELT and DPDPE. A smaller dose of NTB (0.3 mg/kg), which failed to reverse the effects of DPDPE in 100% (4/4) of neurons, effectively antagonized the effects of DELT in 100% (6/6) of neurons. The inhibitory action of DAMGO was completely antagonized by naloxone (0.2 mg/kg) in 100% (6/6) of neurons. The results of the present investigation suggest that: (1) mu-, delta 1- and delta 2-opioid receptors play an important role in the inhibitory modulation of the A delta- and C-fiber-evoked responses of nociceptive neurons in the superficial and deeper dorsal horn of the medulla; (2) selective inhibition of the C-fiber-evoked responses by activation of opioid receptors may account for the opioid-mediated selective suppression of second or persistent pain as compared to first pain; and (3) NTB, in a limited dose range, can discriminate between delta 1- and delta 2-opioid receptor subtypes.

Animals↗

PubMed1996

Salbutamol changes the molecular and mechanical properties of canine skeletal muscle.

1. Salbutamol, a beta 2-agonist, increased the weight of the canine latissimus dorsi muscle. It also increased fusion frequency, and decreased time-to-peak tension, half-relaxation time, and total contraction time. These changes in twitch times and fusion frequency were associated with changes in the levels of proteins expressed in slow- and fast-twitch fibres. Salbutamol decreased the levels of the slow-twitch cardiac isoform of sarco-/endoplasmic reticulum Ca(2+)-ATPase (SERCA2a) and phospholamban proteins, and increased the level of the fast-twitch isoform of sarco-/endoplasmic reticulum Ca(2+)-ATPase (SERCA1a). 2. Changes in the levels of SERCA proteins, particularly SERCA1a, could account for most of the increases in calcium uptake rate observed in homogenates of muscles from the salbutamol-treated animals and could partially account for the changes in half-relaxation rates and other twitch times. 3. Changes in the levels of SERCA1a, SERCA2a and phospholamban protein did not always follow changes in the levels of their corresponding mRNAs. Divergence depended upon the SERCA isoform and muscle. The muscles studied were latissimus dorsi and vastus intermedius. 4. Salbutamol did not change the level of myosin heavy chain (HC)-I isoforms in either muscle, suggesting that it did not increase the proportion of slow-twitch fibres in these muscles. It did increase the level of HC-IIx and decrease the level of HC-IIa isoforms in the latissimus dorsi. Salbutamol did not produce these effects in the vastus intermedius. It is of particular interest that salbutamol changed the relative levels of SERCA proteins in the latissimus dorsi muscle without producing significant change in the level of HC-I isoform.

Adrenergic beta-2 Receptor Agonists↗

PubMed1996

Salbutamol and chronic low-frequency stimulation of canine skeletal muscle.

1. The effect of simultaneous application of chronic muscle stimulation and salbutamol on the expression of mRNAs and proteins normally expressed by fast- or slow-twitch fibres was followed and the effects of changes in protein expression on mechanical performance were evaluated. Chronic low-frequency stimulation increased the myosin heavy chain (HC)-I level in the canine latissimus dorsi muscle and simultaneous administration of salbutamol partially blocked this change. Associated with the increase in HC-I level was a decrease in the velocity of shortening at zero load, VMAX. The change in VMAX was partially blocked by salbutamol. 2. Chronic low-frequency stimulation increased the levels of slow-twitch cardiac isoform sarco-/endoplasmic reticulum Ca(2+)-ATPase (SERCA2a) and phospholamban mRNA, and SERCA2a and phospholamban protein expression. These changes were associated with an increase in time-to-peak tension and a decrease in fusion frequency. Simultaneous administration of salbutamol blocked these changes in protein expression and muscle mechanics. Chronic stimulation of latissimus dorsi decreased the levels of the fast-twitch isoform of sarco-/endoplasmic reticulum Ca(2+)-ATPase (SERCA1a) and increased SERCA2a protein expression and decreased calcium uptake rate by muscle homogenates. These changes were blocked by salbutamol. 3. The loss of latissimus dorsi muscle weight by chronic stimulation was partially blocked by salbutamol.

Adrenergic beta-Agonists↗

PubMed1996

Opioids modulate N-methyl-D-aspartic acid (NMDA)-evoked responses of neurons in the superficial and deeper dorsal horn of the medulla (trigeminal nucleus caudalis).

Extracellular single unit recordings were made from 74 neurons in the superficial and deeper dorsal horn of the medulla (trigeminal nucleus caudalis). N-methyl-D-aspartic acid (NMDA) excited nociceptive as well as non-nociceptive neurons. NMDA receptor antagonist, DL-2-Amino-5-Phosphonovaleric acid (AP-5), blocked the NMDA-evoked excitation. Microiontophoretic application of a selective mu-opioid receptor agonist, [D-Ala2,N-Me-Phe4,Gly5-ol]enkephalin (DAMGO), reduced the NMDA-evoked responses of 100% of nociceptive specific (NS), 93% of wide dynamic range (WDR) and 86% of low threshold (LT) neurons in the superficial and deeper dorsal horn of the medulla. In contrast, application of a selective delta 1-opioid receptor agonist, [D-Pen2,5]enkephalin (DPDPE), reduced the NMDA-evoked responses of 90% of NS neurons, 72% of WDR neurons and 67% of LT neurons in the superficial and deeper dorsal horn of the medulla. DPDPE also produced excitatory or biphasic effects. The inhibitory actions of DAMGO and DPDPE were reversed by naloxone and/or 7-benzylidenenaltrexone (BNTX), mu- and delta 1-receptor antagonists. It is concluded that mu- and delta-opioid receptor agonists produce a predominantly inhibitory modulation of the NMDA-evoked responses of nociceptive and non-nociceptive neurons in the medullary dorsal horn.

Analgesics, Opioid↗

PubMed1996

Nociceptin (orphanin FQ), an endogenous ligand for the QRL1 (opioid-receptor-like1) receptor; modulates responses of trigeminal neurons evoked by excitatory amino acids and somatosensory stimuli.

1. This is the first in vivo electrophysiological evidence demonstrating the effects of Phe-Gly-Gly-Phe-Thr-Gly-Ala-Arg-Lys-Ser-Ala-Arg-Lys-Leu-Ala-Asn-Gln (nociceptin or orphanin FQ), an endogenous ligand for the orphan ORL1 receptor, on nociceptive neurons in the CNS. The effects of nociceptin were tested on the responses of neurons recorded in the superficial and deeper dorsal horn of the medulla (trigeminal nucleus caudalis) in the rat. 2. Nociceptin applied microiontophoretically produced a predominantly long-lasting (5-30 min) inhibitory modulation of the N-methyl-D-aspartic acid (NMDA)-evoked responses of 24 of 31 nociceptive and 12 of 12 nonnociceptive neurons. Excitatory or biphasic effects of nociceptin were also observed in 6 of 43 neurons. Responses evoked by (+/-)-alpha-amino-3-hydroxy-5-methylisox-azole-4-propionic acid (AMPA) were reduced in eight of nine nociceptive and nonnociceptive neurons. 3. The inhibitory effect of nociceptin was not modality specific; responses to both noxious and nonnoxious stimuli were reduced. 4. Although naloxone applied iontophoretically blocked or reduced the peak inhibitory effect of [D-Ala2,N-Me-Phe4, Gly5-ol]-Enkephalin (DAMGO) or trans-(+/-)-3,4-dicholoro-N-methyl-N-(2-1-pyrrolidinyl-cyclo hexyl)-benzene acetamide (U50, 488H), it did not produce a significant alteration in the peak inhibitory effect of nociceptin. 5. Nociceptin administered intracerebroventricularly produced a long-lasting (20-35 min) reduction in the NMDA-evoked responses of three of three nociceptive neurons. 6. Nociceptin produces a predominantly antinociceptive action in the trigeminal system.

Analgesics↗

PubMed1995

Transcriptional regulation of phospholamban gene and translational regulation of SERCA2 gene produces coordinate expression of these two sarcoplasmic reticulum proteins during skeletal muscle phenotype switching.

Chronic 1 Hz stimulation of the canine latissimus dorsi muscle produced a time-dependent switch from the fast-twitch to the slow-twitch phenotype. This included changes in the proteins of the sarcoplasmic reticulum. After 3 days of muscle stimulation, there was down-regulation of fast-twitch Ca-ATPase (SERCA1a) mRNA and induction of slow-twitch Ca-ATPase (SERCA2a) mRNA; most changes in both mRNAs were nearly complete after 14 days of stimulation. Although the induction of phospholamban mRNA began after 3 days of muscle stimulation, its up-regulation was not completed until the muscle had been stimulated for 42 days. The time course of expression of SERCA2a protein was very different from that of SERCA2a mRNA, suggesting that SERCA2 gene expression is regulated at the translational as well as the transcriptional level. The time course of expression of phospholamban protein closely followed that of phospholamban mRNA, suggesting that this gene is under transcriptional control. Thus coordinated expression of SERCA2a and phospholamban proteins is achieved via translational control of the SERCA2 gene and transcriptional control of the phospholamban gene.

Adenosine Triphosphatases↗

PubMed1994

Selective blockade by yohimbine of locus coeruleus-induced inhibition of nociceptive reflex but not that of C responses of spinal dorsal horn neurons in rats.

The effect of alpha 2-adrenoceptor antagonist yohimbine (Yoh) on locus coeruleus (LC)-induced spinal antinociception was investigated in 18 anesthetized Wistar rats. Stimulation of LC markedly inhibited both nociceptive reflex of the posterior biceps semitendinosus (PBST) muscle and C responses of 16 wide-dynamic range (WDR) neurons of the dorsal horn. Application of Yoh (0.2%, 5-10 microliters) to the surface of spinal cord at L3-4 attenuated the LC-induced inhibition of nociceptive reflex without affecting that of C responses of 10 WDR neurons that were tested in 6 rats. The results suggested that LC may exert its inhibitory action on the nociceptive reflex via alpha 2 adrenoceptors somewhere other than the WDR neurons in the spinal dorsal horn.

Adrenergic alpha-2 Receptor Antagonists↗

PubMed1993

VIP-mediated G protein-coupled Ca2+ influx activates a constitutive NOS in dispersed gastric muscle cells.

Vasoactive intestinal peptide (VIP) and peptide histidine-isoleucine (PHI) receptors and the signaling pathways to which they are coupled were characterized in dispersed gastric smooth muscle cells. Radioligand binding using 125I-labeled VIP and PHI identified 4 classes of receptors: VIP-preferring and PHI-preferring receptors recognized by both ligands and readily desensitized by the preferred ligand, and VIP-specific and PHI-specific receptors recognized by only 1 ligand and resistant to desensitization. All except VIP-specific receptors were coupled to adenylate cyclase. VIP-specific receptors mediated a G protein-coupled Ca2+ influx that led to activation of NO synthase (NOS), NO-dependent activation of soluble guanylate cyclase, and activation of guanosine 3',5'-cyclic monophosphate (cGMP) kinase resulting in muscle relaxation. The entire cascade was blocked by Ca2+ channel and/or calmodulin antagonists. The NOS inhibitor NG-nitro-L-arginine abolished L-[3H]citrulline (coproduct of NO synthesis) and cGMP generation and partly inhibited (52 +/- 4%) relaxation. The components of response mediated by VIP-specific receptors (increase in [Ca2+]i, L-[3H]citrulline, and cGMP) were preserved after desensitization. Insertion of guanosine 5'-O-(beta-thio)diphosphate into reversibly permeabilized muscle cells abolished responses mediated by VIP-preferring and VIP-specific receptors. VIP stimulated both adenosine 3',5'-cyclic monophosphate (cAMP)-kinase and cGMP-kinase activities consistent with stimulation of cAMP and cGMP. Both kinases contributed to relaxation that was partly inhibited by cAMP-kinase [H-89 and (R)-p-adenosine 3',5'-cyclic monophosphorothioate] and cGMP-kinase (KT-5823) inhibitors and abolished by a combination of the 2 types of inhibitors. We conclude that VIP-specific receptors mediate a G protein-coupled Ca2+ influx leading to activation of a constitutive Ca2+/calmodulin-dependent NOS and generation of NO, which is partly responsible for relaxation in smooth muscle.

Amino Acid Oxidoreductases↗