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Biomedical subjects

A A Larson

Publications and source records attributed to A A Larson.

119 records · Page 7Linked to original sources
PubMed1980

The role of GABA and serotonin in the mediation of raphe-evoked spinal cord dorsal root potentials.

The possible involvement of bulbospinal serotonergic systems in the mediation of analgesia has created a need for a better understanding of the influence this system has on neuronal mechanisms in the spinal cord. Therefore, these studies were designed to examine the effects of caudal raphe stimulation on primary afferent depolarization and to determine the role of serotonin (5-HT) and GABA in the mediation of these stimulation-produced effects. Stimulation of the raphe evoked two electrotonically conducted dorsal root potentials (DRP-1 and DRP-2) and two compound action potentials (VRP-1 and VRP-2) which were recorded from the dorsal and ventral roots, respectively. Length constant measurements indicated that DRP-1 was generated in group II and DRP-2 in group I primary afferent fibers. Histological determination of stimulation sites revealed that short-latency potentials (DRP-1 and VRP-1) were evoked from many sites within the caudal brain stem, while the long-latency potentials (DRP-2 and VRP-2) were evoked primarily from sites within the caudal raphe nuclei. The role of serotonin in mediating these evoked potentials was assessed by administering various antagonists of serotonin (cinanserin, methysergide and D-lysergic acid diethylamide). These agents consistently attenuated the long-latency potentials (DRP-2 and VRP-2) but increased the magnitude of DRP-1. The possibility of a GABAergic neuron in the descending systems projecting to primary afferent terminals was studied. Depletion of GABA by semicarbazide blocked DRP-1, but had only a modest effect of DRP-2. However, the putative GABA antagonist, bicuculline, inhibited both DRP-1, and DRP-2. These results suggest that a GABA interneuron is not involved in the bulbospinal serotonergic depolarization of primary afferent terminals. This system appears to constitute a presynaptic filter of afferent input, with the capacity to inhibit different fiber groups.

Afferent Pathways↗
PubMed1980

The potentiation of spinal analgesia by leucine enkephalin.

In two strains of rats, intrathecal administration of morphine and met-enkephalin was found to produce a dose-dependent analgesic effect as measured by the tail-flick assay. Prior administration of leu-enkelphalin at a dose which had no analgesic effect was found to reduce significantly the analgesic ED50 of both morphine and met-enkephalin. Met-enkephalin pretreatment, at a similar sub-analgesic dose, was without effect. Thus, a differential interaction of the enkephalins with morphine is evident at spinal structures.

Anesthesia, Spinal↗
PubMed1979

Changes in primary afferent depolarization after administration of gamma-acetylenic gamma aminobutyric acid (GAG), a gamma-aminobutyric acid (GABA) transaminase inhibitor.

gamma-Acetylenic gamma-aminobutyric acid (GAG), an irreversible inhibitor of GABA transaminase, increased the concentration of GABA in feline spinal cords to 239% of the control value by 225 min after its injection. After administration of GAG to spinally transected cats, the height of the segmentally evoked dorsal root potential (DRP), which is generated at one point via a GABA synapse, was increased to more than twice the control value although the area increased only slightly. However, GAG had no effect on the segmental DRP in the decerebrate cat. In contrast, the DRP evoked in decerebrate cats by electrical stimulation of the brain stem, which is probably mediated by GABA, was decreased by administration of GAG. These effects of GAG were accompanied by the development of spontaneous primary afferent depolarizations which resembled spontaneous DRPs in both spinal and decerebrate cats. The temporal and size correlation between spontaneous DRPs occurring in different spinal roots indicate they are generated by an interneuronal pathway that is released by the action of GAG. The action of GAG on the segmental DRP in the spinal but not decerebrate preparation is also most easily explained by GAG-induced effects on interneuronal pathways. These data suggest GABA transaminase inhibition does not affect the axoaxonic GABA synapse mediating the DRP.

4-Aminobutyrate Transaminase↗
PubMed1977

Effect of narcotics on the uptake of serotonin precursors by the rat brain.

The extraction of 14C-tryptophan and 14C-hydroxytryptophan (5-HTP) from the blood to the brain was measured using an indicator dilution technique. Acute treatment with morphine caused a dose-related decrease in the extraction of tryptophan by the brain and a increase in that of 5-HTP. Naloxone alone had no effect on the extraction of either tryptophan or 5-HTP but completely blocked the effect of 20 mg/kg of morphine on the extraction of both tryptophan and 5-HTP. In contrast to acute treatment with morphine, the extractions of tryptophan and 5-HTP were not significantly altered 48 hours after chronic treatment with morphine. The extraction of 5-HTP remained unchanged and that of tryptophan increased significantly 72 hours after chronic morphine treatment. In equivalent doses, levorphanol decreased the extraction of tryptophan more than its inactive isomer, dextrorphan, whereas levorphanol increased and dextrorphan had no effect on the extraction of 5-HTP. These results suggest that an increase in the rate of central serotonin synthesis after acute treatment with morphine may be due to an increased uptake of 5-HTP from the blood to the brain while that after chronic treatment with morphine may be due to an increased uptake of tryptophan.

5-Hydroxytryptophan↗
PubMedDate not supplied

Modulation of [3H]DAGO binding by substance P (SP) and SP fragments in the mouse brain and spinal cord via MU1 interactions.

Binding of [3H]DAGO to fresh, frozen or beta-funaltrexamine (beta-FNA) pretreated membranes of mouse brain and spinal cord was extensively studied using substance P (SP) or SP fragments as potential competitors and/or modulators. The objective was to determine whether SP exerts its analgesic effect by interacting with mu opioid receptors. The affinity of DAGO was reduced and binding capacity was increased in the presence of SP or the N-terminal SP fragments SP(1-9) and SP(1-4) but not the C-terminal SP fragment SP(5-11). Because sub-nanomolar concentrations of SP or N-terminal SP fragments displaced [3H] DAGO binding to a minor but detectable degree, it is suggested that SP interacts with mu 1 sites through its N-terminus portion. The effect of SP on DAGO binding was less in the spinal cord compared to the rest of the brain. Modulation of DAGO binding by SP was enhanced in the brain after pretreatment of membranes with the narcotic antagonist beta-FNA. These results suggest a novel mechanism for the analgesic action of SP.

Animals↗
PubMedDate not supplied

Substance P modulation of DAMGO binding in the brain of CXBK and Swiss-Webster mice.

The effects of substance P (SP) on the binding of the selective mu opioid agonist [3H]DAMGO to brain membranes of CXBK and Swiss-Webster (SW) mice were compared. We have previously shown that subnanomolar concentrations of SP and N-terminal fragments of SP modulate DAMGO binding in SW brain membranes and hypothesized that modulation occurs via SP interaction with mu 1 sites. In the present study, binding assays using CXBK mice, a strain deficient in mu receptors including mu 1 sites, were performed to assess the effect of mu receptor deficiency on SP-induced modulation of DAMGO binding. Whereas the addition of 0.1 nM SP to the binding mixtures produced up to 30% increase in the values of Kd and maximum binding capacity (R) for the SW strain, SP produced little or no change in the case of CXBK strain. Maximum binding capacity for DAMGO was 43% less in the brain of CXBK mice than in SW mice. No difference was observed in the estimated binding parameters of the spinal cord for the two strains. Whereas pretreatment of brain membranes of SW mice using beta-funaltrexamine (beta-FNA) increased from 2- to 10-fold the modulatory effect of SP, CXBK brain membranes pretreated with beta-FNA remained nearly insensitive to modulation by SP. The effect of SP on the affinity of DAMGO binding in SW mice, but not in CXBK mice, was reversed by the addition of GTP. It is concluded that mu receptor deficiency can markedly influence SP-induced modulation of DAMGO binding.

Animals↗
PubMedDate not supplied

Correlation of substance P-induced desensitization with substance P amino terminal metabolites in the mouse spinal cord.

Intrathecal injection of mice with substance P (SP) or its C-terminal fragments results in a behavioral syndrome characterized by reciprocal caudally directed biting and scratching. Repeated injection of SP, but not SP C-terminal fragments, results in a decrease in the intensity of, or desensitization to, these SP-induced behaviors. Peptidase inhibitors, phosphoramidon (PH), bacitracin (BAC), diprotin A (DPA) and angiotensin converting enzyme inhibitor (ACEI OR SQ20881), together with [3H]SP, were used to investigate the possible accumulation of tritiated N-terminal metabolites in the mouse spinal cord in vivo during the development of desensitization to SP. SP N-terminal metabolites in the spinal cord were quantified by reverse-phase HPLC. The magnitude of SP-induced desensitization correlated well (r = .95) with total SP N-terminal metabolites recovered from the spinal cords of the same mice studied in vivo. The magnitude of SP-induced desensitization was also found to be negatively correlated (r = .95) with total recovered intact [3H]SP. The rank order of potency of the peptidase inhibitors in decreasing the magnitude of SP-induced desensitization was BAC = PH much greater than ACEI greater than DPA. The order of potency for in vitro inhibition of SP metabolism using synaptic membrane-derived peptidases was BAC greater than PH much greater than ACEI. These results support the hypothesis that desensitization to SP-induced behaviors depends, at least in part, on the concentration of SP N-terminal metabolites in the spinal cord.

Amino Acid Sequence↗
PubMedDate not supplied

DAMGO binding to mouse brain membranes: influence of salts, guanine nucleotides, substance P, and substance P fragments.

Substance P (SP) appears to mediate many processes of the central nervous system, including pain. This report deals with modulation of opioid binding in the mouse brain by SP and SP fragments, as well as by salts and guanine nucleotides. Binding studies of the selective mu opioid receptor agonist [D-Ala2, MePhe4,Gly(ol)5]enkephalin (DAMGO) to mouse brain membrane preparations demonstrated that guanine nucleotide modulation of DAMGO binding affinity was modified by SP. However, SP had little or no influence on inhibition of DAMGO binding induced by salts, such as MgCl2, CaCl2, or NaCl. By replacing GTP with GppNHp, SP (0.1 nM) produced multiple affinity forms of the DAMGO receptor, while at a higher concentration (10 nM), SP lost its influence on DAMGO binding. Furthermore, 0.1 nM SP changed DAMGO binding parameters in a medium containing NaCl, CaCl2, and GppNHp such that the high- and low-affinity conformations of the receptor converted to a single site following the addition of SP to the incubation medium. While the C-terminal SP fragment SP(5-11) was without effect, the N-terminal SP fragments SP(1-9) and SP(1-7) appeared to imitate SP in modifying GppNHp-modulated DAMGO binding. These results suggest that SP functions as a modulator of opioid binding at the mu receptor and it appears that the N-terminus of SP plays a role in the modulatory process.

Animals↗