Receptor mechanisms for nociception.
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Analgesics, Opioid↗
Biomedical subjects
L Terenius
Publications and source records attributed to L Terenius.
Topography of NPY-, somatostatin-, and VIP-immunoreactive, neuronal subpopulations in the guinea pig celiac-superior mesenteric ganglion and their projection to the pylorus.
The topography of the peptidergic neuronal subpopulations in the guinea pig celiac-superior mesenteric ganglion was studied analyzing the distribution of immunoreactivity to neuropeptide Y (NPY), somatostatin (SOM), and vasoactive intestinal polypeptide (VIP)/polypeptide HI (PHI). For comparison, the ganglion was also studied using antisera against the 2 catecholamine-synthesizing enzymes tyrosine hydroxylase (TH) and dopamine beta-hydroxylase (DBH). Approximately 65% of the neuronal cell bodies contained NPY-like immunoreactivity (NPY-LI), whereas 25% of the principal ganglion cells contained SOM-like immunoreactivity (SOM-LI). Though occasional cells were found to contain both NPY-LI and SOM-LI, these peptides had a complementary distribution in the ganglion, with NPY cells in the celiac poles and SOM cells in the superior mesenteric pole. The vast majority of both the NPY- and SOM-positive cells also contained TH-like immunoreactivity (TH-LI), confirming their catecholaminergic, presumably noradrenergic, nature. Some noradrenergic neurons seemed to lack NPY- and SOM-LI. Small numbers of VIP/PHI-containing cell bodies were found in areas where the NPY-immunoreactive neurons predominated. Many of the VIP/PHI-positive cells contained NPY-LI and occasionally also TH-LI. The immunohistochemical markers were also observed in fibers. Thus, a comparatively weak NPY-LI was seen in smooth fibers, probably representing axons and axon bundles. SOM-LI was seen in a similar type of fiber but also in more strongly fluorescent fibers with a varicose appearance. The latter fibers were observed only in the SOM-dominated part of the ganglion, often surrounding the ganglion cells. Varicose fibers with a similar distribution containing DBH-like immunoreactivity (DBH-LI) were also seen. In addition, DBH- and TH-LI were seen in smooth axonlike processes. VIP-positive fibers exhibited a very dense fiber network, almost exclusively related to the SOM cell-dominated part of the ganglion. The projection of the postganglionic sympathetic neurons was studied with special reference to the pylorus using a combination of retrograde axonal tracing and indirect immunofluorescence techniques. Seventy-two hours after injection of the fluorescent tracer Fast Blue into the pyloric sphincter, labeled neurons were found in the ganglion. By comparing the Fast Blue-labeled cells with the immunoreactive cell bodies, neurons containing both dye and NPY- or SOM-LI were observed. In elution-restaining experiments, it was established that the majority of these cells were also immunoreactive to TH, indicating that they produce noradrenaline.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
Assay and biochemical characterization of a dynorphin converting enzyme in human cerebrospinal fluid.
An endopeptidase hydrolyzing dynorphins A and B and alpha-neo-endorphin at the Arg6-Arg7 or Arg6-Lys7 bonds, was partially purified from human cerebrospinal fluid and further characterized by various biochemical techniques including HPLC gel permeation (UltroPac TSK G3000SW) and ion exchange (TSK DEAE-3SW) chromatography. A procedure for quantitative analysis of the enzyme in individual CSF samples is also described. The activity in lumbar CSF of women in late pregnancy was significantly lower than that in control samples.
Amino Acid Sequence↗
Neuropeptide Y receptor interaction with beta-adrenoceptor coupling to adenylate cyclase.
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Adenylyl Cyclases↗
[Met]enkephalin-Arg6-Phe7 in human CSE--increased levels in late pregnancy.
The opioid heptapeptide, [Met]enkephalin-Arg6-Phe7 was measured in CSF of women at term pregnancy and during the luteal phase by RIA. Levels turned out to be significantly increased in pregnant women. These results are in agreement with an earlier paper in which we reported increased levels of receptorassayed opioid peptides deriving from proenkephalin A in CSF of women in term pregnancy compared to levels in nonpregnant, nonpuerperal women.
Chromatography, High Pressure Liquid↗
Neuropeptide Y-like immunoreactivity in the lumbosacral pia mater in normal cats and after sciatic neuroma formation.
An indirect immunohistochemical technique was used to identify neuropeptide Y (NPY)-immunoreactive nerve fibers in the lumbosacral pia mater of normal cats and in kittens previously subjected to sciatic nerve resection. It was shown that NPY-positive fibers both associated with blood vessels and lacking vascular relation occur in the pia mater of normal cats. After nerve lesion some fibers which were not associated with blood vessels ramified extensively in the pia mater and formed thin beaded branches which ended blindly.
Amputation Stumps↗
High enkephalyl peptide degradation, due to angiotensin-converting enzyme-like activity in human CSF.
The metabolism of enkephalin peptides was studied in human cerebrospinal fluid. The degradation rates of (Leu)-enkephalin and (Leu)-enkephalin-Arg6 were compared and the latter was degraded at a 10-fold higher rate. The major enzyme activity was investigated by Mr determination and inhibition experiments, showing marked similarity with angiotensin-converting enzyme.
Chromatography, High Pressure Liquid↗
Endopeptidase in human cerebrospinal fluid which cleaves proenkephalin B opioid peptides at consecutive basic amino acids.
An endopeptidase releasing the common N-terminal hexapeptide, (Leu)-enkephalin-Arg6, from dynorphins A and B, and alpha-neoendorphin was purified from human cerebrospinal fluid. Purification involved ion-exchange chromatography (DEAE-Sepharose CL-6B), hydrophobic interaction chromatography (phenyl-Sepharose CL-4B) and molecular sieving (Sephadex G-100). The enzyme showed molecular heterogeneity. A major fraction had an apparent molecular weight of about 40,000. It had an optimum activity in the pH range of 6-8. The conversion of dynorphin A was not affected by EDTA or iodoacetate but strongly reduced in the presence of phenylmethyl-sulphonyl fluoride, suggesting the enzyme is a serine protease.
Amino Acids↗
Calcitonin gene-related peptide is a potent inhibitor of substance P degradation.
Calcitonin gene-related peptide (CGRP) was found to potently inhibit a substance P endopeptidase isolated from human CSF. CGRP potentiated substance P irritant actions; a possible mechanism is interaction for a common metabolic step. Somatostatin is another peptide capable of competing with substance P endopeptidase.
Calcitonin Gene-Related Peptide↗
Immunohistochemical demonstration of some putative neurotransmitters in the lamprey spinal cord and spinal ganglia: 5-hydroxytryptamine-, tachykinin-, and neuropeptide-Y-immunoreactive neurons and fibers.
The distribution of some putative neurotransmitters was investigated in the spinal cord and spinal ganglia of the lamprey, a primitive vertebrate, by using immunohistochemical methods. In the spinal cord a midline row of 5-hydroxytryptamine (5-HT)-immunoreactive neurons was present immediately ventral to the central canal over the entire length of the spinal cord. The ventral processes of these neurons formed a dense ventromedial plexus of varicosities. In the dorsal, lateral, and ventral spinal axon columns, several longitudinal 5-HT fibers were present. After chronic spinal transections the distribution of 5-HT fibers was unchanged; it is therefore concluded that there was no substantial descending 5-HT contribution and that the spinal 5-HT neurons supplied the regional 5-HT innervation. The spinal 5-HT cells sent fibers into the dorsal and ventral roots; 5-HT cell bodies and fibers were also present in the spinal dorsal root ganglia, in their dorsal, ventral, and lateral nerve branches, and in the dorsal and ventral branches of the ventral roots. Neurons and fibers containing peptides of the tachykinin (TK) family (to which, amongst others, substance P belongs) were found in the spinal cord. TK neurons in the spinal cord supplied the local TK innervation, as well as TK fibers in the dorsal and ventral roots. Fibers have been found containing either TK, or 5-HT, or both compounds. Neurons containing neuropeptide-Y (NPY)-immunoreactive material were present in a medial column just dorsal to the central canal. The NPY neurons have longitudinal, mainly descending, fibers that provide the local NPY innervation of the lamprey spinal cord. The present results provide evidence for local spinal systems containing 5-HT, TK, 5-HT and TK, or NPY, but in contrast to mammals, these compounds do not seem to arise from supraspinal neurons.
Animals↗
Fusion transfer of dopamine DA1 receptors to Friend erythroleukemia cells.
Dopamine DA1 receptors were transferred from rat striatal membranes to Friend erythroleukemia cells (Fc) by membrane fusion. The Fc cells lack DA1 receptors but have a functional adenylate cyclase system. The striatal membranes bearing DA1 receptors were treated with N-ethylmaleimide (NEM) prior to fusion to inactivate their intrinsic adenylate cyclase activity. Fusion of the NEM-treated membranes and the Fc cells was induced by polyethylene glycol treatment to form a functional system de novo, which could be demonstrated by measuring the increase in cAMP production after addition of dopamine. This method provides a possibility to study the functional competence of receptors in neural tissue in more detail.
Animals↗
Endorphin activity in childhood psychosis. Spinal fluid levels in 24 cases.
Twenty 2- to 13-year-old infantile autistic children (16 boys and four girls) and four 4- to 13-year-old children (two boys and two girls) with other kinds of childhood psychoses were compared with eight 6-month-old to 6-year-old normal children with regard to cerebrospinal fluid contents of endorphin fractions I and II. The psychosis groups showed higher mean cerebrospinal fluid endorphin fraction II levels, and 11 (55%) of the 20 autistic patients showed values higher than the highest in the group of normal children. There was a trend toward a correlation between high fraction II levels and self-destructiveness and decreased pain sensibility in the psychotic children. The results are regarded as preliminary but as warranting further research in this potentially fruitful field.
Adolescent↗
Agonist-antagonist properties of fluorescent opioid probes in the guinea-pig myenteric plexus-longitudinal muscle preparation.
The opioid activity of a series of fluorescent derivatives of oxymorphone, naloxone and naltrexone, were characterized on the electrically stimulated guinea-pig myenteric plexus-longitudinal muscle preparation. In all compounds the fluorescent moiety, fluorescein or tetramethylrhodamine B, is attached to the C-6 carbon of the morphinan. Mu-receptor affinity was well retained and there was a good correlation between capacity to displace [3H]-dihydromorphine from binding sites in rat brain membranes and apparent receptor affinity in the myenteric plexus measured as antagonism of normorphine effects. Fluorescein conjugated oxymorphone showed mainly agonist activity. Certain derivatives of the antagonists naloxone and naltrexone showed partial agonism. One compound, 1-(N)-fluoresceinyl naloxone thiosemicarbazone, was an antagonist.
Animals↗
Neuropeptide Y (NPY)-like immunoreactivity in guinea pig uterus is reduced during pregnancy in parallel with noradrenergic nerves.
Neuropeptide Y (NPY) is a recently discovered neuropeptide with vasoconstrictor effects when given in vivo. It occurs in many sympathetic neurons, where it appears to coexist with noradrenaline (NA). It is wellknown that profound changes in the levels of uterine NA occur in many species during pregnancy. Therefore we have investigated the distribution of catecholamine neurons and NPY by immunohistochemistry in the pregnant and nonpregnant guinea pig uterus. In the virgin uterus NPY-like immunoreactivity was present in nerve fibres and terminals in the smooth muscle layers of the uterine horns and around blood vessels. The distribution of NPY fibres was very similar to that of noradrenergic nerves visualized with antibodies against the catecholamine synthesizing enzyme tyrosine hydroxylase (TH). In the pregnant uterus, NPY- and TH-like immunoreactivity disappeared almost completely. In the cervix, a slight decrease of immunoreactivity was observed, whereas in the ovaries no changes were noted between the pregnant and nonpregnant condition. The results indicate that NPY and catecholamines coexists in the adrenergic neurons of the guinea pig uterus, cervix and ovary and that they vary together in the myometrium during pregnancy. We suggest that NPY may be of functional importance for the pregnant uterus.
Adrenergic Fibers↗
Differential effects of reserpine and 6-hydroxydopamine on neuropeptide Y (NPY) and noradrenaline in peripheral neurons.
The effects of 6-hydroxydopamine (6-OHDA) and reserpine pretreatment on peripheral neuropeptide Y (NPY)- and noradrenaline (NA)-containing neurons were studied in guinea-pigs. Ten days after 6-OHDA pretreatment, a 60-80% reduction of the NA content was observed in the right atrium of the heart, stellate ganglion and spleen. The content of NPY-like immunoreactivity (LI) was reduced by about 50% in the heart, not changed in the spleen while it increased to 200% of control in the stellate ganglion. Immunohistochemistry showed a pronounced loss of NPY- and tyrosinehydroxylase (TH)-immunoreactive (IR) nerves in the heart but not in the spleen. Increased NPY-IR was seen in axons and cell bodies of the stellate ganglion. Reserpine pretreatment (thereshold dose 0.5 mg X kg-1) caused a dose- and time-dependent reduction of the content of NPY-LI in the heart. A maximal depletion of NPY-LI (about 80%) was observed 5 days after reserpine. Reserpine pretreatment also reduced the content of NPY-LI in the spleen, while no significant change was observed in the adrenal gland or vas deferens. The levels of NPY-LI increased in the stellate ganglion to about 180% of control 5 days after reserpine. Immunohistochemical analysis revealed an almost total loss of NPY-IR nerve fibres in the heart as well as around blood vessels in the lung and skeletal muscle. No detectable changes were observed in perivascular NPY-IR nerves in the spleen, vas deferens or kidney. TH-IR nerves remained unchanged after reserpine, thus indicating that the observed loss of NPY-IR nerves was due to a depletion of NPY and not a degeneration. No change in the levels of substance P-LI was observed in the right atrium 5 days after reserpine. NA was, in contrast to NPY, markedly depleted in all tissues investigated after reserpine treatment. The depletion of NA was more extensive, and occurred more rapidly and at much lower doses as compared to the effects on NPY-LI. Ligations of the sciatic nerve revealed that NPY-LI was transported axonally with a rapid rate (3 mm/h). Reserpine pretreatment significantly increased the amount of accumulated NPY-IR above the ligation, suggesting an increase in axonal transport. High performance liquid chromatography revealed that the NPY-LI consisted of two major peaks in the stellate ganglia, while only one peak closely corresponding to porcine NPY was seen in the right atrium. In conclusion, 6-OHDA pretreatment depletes NPY-LI in certain terminal regions and increases NPY-LI in ganglia.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
The histamine-releasing effect of dynorphin and other peptides possessing Arg-Pro sequences.
The basic opioid peptide dynorphin was tested for histamine-releasing activity on peritoneal rat mast cells. Dynorphin was found to induce a dose-dependent histamine release from the mast cells. The threshold concentration was 2 X 10(-7) M and release was maximal (40% of total) at 2 X 10(-6) M of the peptide. The dynorphin-induced histamine release was a very rapid process completed within 10 seconds at 37 degrees C. The release was independent of extracellular calcium. Experiments with naloxone and a specific kappa-agonist (U-50,488H) gave results indicating that the dynorphin induced histamine release was probably not mediated through opioid kappa-receptors. A couple of other Arg-Pro containing peptides of different origin were also screened for histamine-releasing activity. Most of these peptides elicited a more or less pronounced histamine release, provided the peptide contained more than 5 amino acids, suggesting that the Arg-Pro sequence is of importance for the histamine-releasing effect of peptides such as dynorphin.
Amino Acid Sequence↗
Long-term high frequency transcutaneous electrical nerve stimulation (hi-TNS) in chronic pain. Clinical response and effects on CSF-endorphins, monoamine metabolites, substance P-like immunoreactivity (SPLI) and pain measures.
Eighteen patients with chronic pain syndromes of organic origin were treated by means of high frequency transcutaneous nerve stimulation (hi-TNS). The CSF levels of receptorassayable Fraction I and II endorphins, substance P-like immunoreactivity (SPLI), and the monoamine metabolites 5-HIAA, HVA and MOPEG were measured before and after one week of daily treatment. Furthermore, the effects on experimental pain measures were determined. The therapeutic effect was evaluated after 30 days and 3 months of treatment. Patients with low initial concentrations of endorphins in CSF, lower than those observed in healthy volunteers, tended to have the best response to hi-TNS. There were significant increases in Fraction I endorphins and SPLI in CSF, most pronounced in the patients who responded. There were no significant changes in 5-HIAA, HVA or MOPEG in CSF. However, in early responders, the serotonin metabolite 5-HIAA tended to decrease as contrasted to an increase in non-responders. The difference between the groups was statistically significant. Confirming our earlier studies, the therapy induced changes in pain measures showed a significant, positive correlation with increasing Fraction I endorphins in CSF. Our results suggest that hi-TNS induces central changes in the endorphinergic, serotonergic and possibly substance-P-ergic systems.
Adult↗
Identification of high molecular weight enkephalin percursor forms in human cerebrospinal fluid.
An enzyme radioimmunoassay procedure has been used to identify (Leu)- and (Met)enkephalin containing polypeptides in human cerebrospinal fluid (CSF). A large volume of lumbar CSF collected from 15-20 neurologic subjects was fractionated by ion exchange chromatography on Aminex Q-15 and subsequently on Sephadex G-50. The lyophilized fractions were treated with trypsin and the generated enkephalyl hexapeptides were isolated by SP-Sephadex ion-exchange chromatography and quantified by radioimmunoassay specific for (Met)enkephalin-Arg6/Lys6 and (Leu)enkephalin-Arg6, respectively. Confirmation of the structures of the recovered fragments was obtained by HPLC. In total, the procedure yielded about 100 fmole (Met)-enkephalyl and 40 fmole (Leu)enkephalyl hexapeptides per ml CSF. Our results also suggest that the main part of the (Leu)enkephalin related activity emerged from prodynorphin.
Amino Acid Sequence↗