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Biomedical subjects

S J Enna

Publications and source records attributed to S J Enna.

At least 37 records · Page 2Linked to original sources
PubMed1999

Nociceptive regulation of GABA(B) receptor gene expression in rat spinal cord.

Activation of gamma-aminobutyric acid (GABA) neurotransmission evokes antinociceptive responses in laboratory animals. The recent cloning of GABA(B) receptor gene products makes it possible to examine the regulation of this receptor system as it relates to the mediation of pain-related sensory information. Inasmuch as acute and chronic pain alter the expression of a number of nociception-related receptors, and because such changes are important components in the regulation of pain, the present study was undertaken to determine whether GABA(B) receptor gene expression is altered in sensory systems following a peripheral nociceptive stimulus. Solution hybridization-nuclease protection assays conducted 24 h after formalin injection into the right hindpaw of the rat revealed a significant bilateral increase in GABA(B) R1 and R2 receptor expression in the dorsal lumbar spinal cord, and a significant increase in GABA(B) R1 receptor mRNA in the ipsilateral lumbar dorsal root ganglion. These findings indicate an activity-dependent, differential regulation of GABA(B) R1 and R2 receptor gene expression in spinal sensory systems in response to chemogenic nociceptive activation, suggesting that GABA(B) receptor plasticity may play an important role in regulating the mediation, and perception, of chronic pain.

Animals↗
PubMed1998

Regulation of neurokinin-1 receptor expression by GABA(B) receptor agonists.

Activation of GABA(B) receptors produces analgesia in acute and chronic pain models. Data indicate that a possible mechanism for this effect is a GABA(B) receptor-induced blockade of neurokinin-1 (NK-1) receptor gene expression in the spinal cord. While much more potent GABA(B) receptor agonists (CGP 44532) have been developed, there is no information on their antinociceptive properties or their ability to influence NK-1 receptors. To address these issues, rats were treated with baclofen or CGP 44532 and tested for sedation, ataxia, and pain-related behaviors in a chronic pain model (formalin hindpaw injection). In a separate group of experiments the analgesic response to a single dose of CGP 44532 was tested prior, and subsequent to, its chronic administration. The results indicate that CGP 44532 is a substantially more potent analgesic than baclofen. In addition, after chronic administration baclofen was no longer capable of inducing analgesia or of inhibiting the increased expression of NK-1R mRNA and CGP 44532 was still fully effective in both regards. The results suggest that GABA(B) agonists could be clinically useful analgesics.

Animals↗
PubMed1997

GABAB receptor agonists and antagonists: pharmacological properties and therapeutic possibilities.

Gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter, is widely distributed throughout the brain and spinal cord. Two major families of GABA receptors have been identified, GABAA and GABAB. While much is known about the pharmacological and molecular properties of GABAA receptors, it is only within the last few years that potent and selective antagonists have been developed for the GABAB site, and only within the past few months that this receptor has been cloned. Thus, tools are now available to define more fully the GABAB receptor in terms of its biology and the therapeutic potential of manipulating this site. Data suggest that, in addition to their established use as muscle relaxants, GABAB receptor agonists possess analgesic and antitussive properties, and may be useful for treating bladder dysfunction. While there is less clinical data on GABAB receptor antagonists, preclinical results indicate that they may be of value in treating absence epilepsy, cognitive dysfunction and, possibly, pulmonary and intestinal disorders. However, for this potential to be fully exploited, it is necessary to identify and characterise molecularly and pharmacologically distinct GABAB receptor subtypes.

Editorial↗
PubMed1996

Evidence for pharmacologically distinct GABAB receptors associated with cAMP production in rat brain.

Gamma-Aminobutyric acid-B (GABAB) receptors mediate a variety of cellular functions, suggesting the possibility of pharmacologically and molecularly distinct receptors. To explore this possibility a number of GABAB receptor agonists and antagonists were examined for their ability to influence cAMP production in rat brain cerebral cortical slices. While the agonists did not differentiate between receptors associated with the augmentation of isoproterenol-induced cAMP production and those mediating inhibition of forskolin-stimulated second messenger accumulation, significant differences were noted between the potencies of some antagonists to inhibit these GABAB receptor-mediated responses. The results suggest at least two pharmacologically distinct subclasses of GABAB receptors regulate cAMP production in brain.

Adrenergic beta-Agonists↗
PubMed1994

Excitatory amino acid receptors: a gallery of new targets for pharmacological intervention.

The excitatory amino acids (EAAs) L-glutamate and L-aspartate are the most abundant amino acids in brain and play a number of roles in maintaining neuronal function. Among these are their use as protein constituents, as key intermediates in ammonia metabolism, and as precursors for other neurotransmitters. Given the widespread distribution of EAA-containing neurons, these transmitters are likely to be involved in virtually all central nervous system functions, with abnormalities in neurotransmission contributing to the symptoms of a host of neurological and psychiatric disorders. Because of the importance of EAAs in maintaining the functional integrity of the central nervous system, efforts are underway to design agents capable of regulating the activity of these transmitters for therapeutic gain. Inasmuch as potential side effects preclude a generalized modification of this system, strategies must be found to alter EAA neurotransmission in selected brain regions. In this regard, pharmacological data suggest several functionally distinct EAA receptors, a finding confirmed by cloning studies which hint at an even larger family of sites. Moreover, it appears that some excitatory amino acid receptor complexes are composed of interacting sites which orchestrate receptor function, and there is evidence that EAA receptors may influence the activity of one another. Thus, there appear to be numerous sites that can be targeted to selectively modify excitatory amino acid neurotransmission in brain. Besides the agonist recognition site for each receptor subtype, other targets include regulatory subunits, ion channels and components of receptor-coupled second messenger systems.

Animals↗
PubMed1993

Gamma-aminobutyric acidA receptor subunits in the mediation of selective drug action.

Pharmacologic and biochemical data indicate a variety of gamma-aminobutyric acidA receptor subtypes. The identification of gamma-aminobutyric acidA receptor subunits and their isoforms has yielded a more refined characterization of the pharmacologic selectivity of these sites. Such structural diversity may explain the different responses noted with drugs acting through gamma-aminobutyric acidA receptors and makes possible the design of new agents capable of selectively manipulating this neurotransmitter system.

Animals↗
PubMed1991

(+/-)-Terodiline: an M1-selective muscarinic receptor antagonist. In vivo effects at muscarinic receptors mediating urinary bladder contraction, mydriasis and salivary secretion.

The affinity and selectivity of racemic terodiline (N-tert-butyl-1-methyl-3,3-diphenylpropylamine HCl) for muscarinic receptor subtypes was determined from functional responses of rabbit vas deferens (M1), guinea pig atria (M2) and bladder detrusor muscle (M3). (+/-)-Terodiline was found to be about as potent as pirenzepine in the rabbit vas deferens (Kb = 15 and 31 nM, respectively) and at least as selective for M1 relative to M2 (11-fold) and M3 (19-fold) receptors. Like pirenzepine, (+/-)-terodiline does not distinguish between M2 and M3 receptors in vitro. The peripheral actions of (+/-)-terodiline were evaluated in vivo in terms of its ability to induce mydriasis, and to inhibit salivary secretion and urinary bladder contraction. (+/-)-Terodiline given s.c. was equipotent in inhibiting intravesical bladder pressure and carbachol-induced salivary secretion (ID50 = 24 and 35 mg/kg, respectively), and in increasing pupil diameter (ED50 = 59 mg/kg). These results suggest that the in vivo actions of racemic terodiline at (M3) receptors mediating bladder contraction may not be separable from its actions at receptors mediating mydriasis and salivation. Moreover, its effects on the pupil and salivary glands are apparently not mediated through M1 receptors. Together, these findings help clarify the action of (+/-)-terodiline in the treatment of neurogenic bladder.

(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethy↗
PubMed1991

Pharmacological characterization of sigma binding sites in guinea pig brain membranes.

The discovery of sigma binding sites has prompted investigation into the functional role of these sites. Binding studies have revealed that sigma sites exhibit a unique pharmacological profile, and have provided evidence favoring the existence of a multiplicity of sigma binding sites in central nervous system. However, the findings that chemicals having diverse structures and therapeutic applications are all potent sigma agents, and that sigma binding sites are present in peripheral tissues, have raised concerns about the physiological and pharmacological relevances of this site. Furthermore, an endogenous ligand for the sigma binding site has not yet been identified. Finally, there is a lack of data regarding the functional coupling of sigma binding sites, although recent studies have provided some clues as to a possible signalling mechanism (Karbon et al., 1990). Besides raising questions about the relevance of sigma sites, the paucity of information on their functional properties has made it difficult to distinguish sigma agonists from and antagonists. While haloperidol is assumed to be a sigma antagonist, the finding that prolonged administration of this neuroleptic decreases the number of sigma sites would seem to argue in favor of it being an agonist for this site. Regardless of the precise nature of the sigma binding site, studies have suggested that it may represent the site of action for a number of important drugs. For example, haloperidol, a butyrophenone antipsychotic, exhibits high affinity for sigma binding sites, and several psychotomimetics, including PCP and (+)-benzomorphans, also bind this site.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Biochemical and behavioral studies following subchronic administration of GABA uptake inhibitors in mice.

N-(4,4-Diphenyl-3-butenyl) nipecotic acid (SKF(R)-89976A) and N-(4,4-diphenyl-3-butenyl) guvacine (SKF 100330A) are potent inhibitors of the uptake of GABA and have anticonvulsant properties. In the present study, the effects of these compounds on several behavioral and biochemical measures were determined, following subchronic administration. Administration of SKF(R)-89976A (8.9 mg/kg) for 14 days caused a small but significant reduction in its potency to protect against pentylenetetrazole-induced seizures, whereas treatment with SKF 100330A (13.6 mg/kg) had no significant effect. The percentage of animals rendered cataleptic by administration of either GABA uptake inhibitor was reduced by treatment for as few as 4 days and treatment with SKF(R)-89976A for 14 days resulted in a 4-fold increase in the CD50 for induction of catalepsy. The binding of [3H]GABAA and [3H]GABAB in membranes from the forebrain of the mouse were not influenced by treatment with drug nor was synaptosomal uptake of [3H]GABA. Likewise, the binding of [3H]sulpiride in striatal membranes of the mouse was unaffected by repeated exposures to SKF(R)-89976A. These results demonstrate that prolonged administration of GABA uptake inhibitors produced only a small reduction in anticonvulsant potency, whereas liability to side-effects, as demonstrated by the reduction in catalepsy, was substantially reduced.

Animals↗
PubMed1989

An in vivo procedure for the selective inactivation of rat brain cerebral cortical alpha-adrenoceptors using N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ).

Intraperitoneal administration of 0.8 mg/kg N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) to rats significantly reduced alpha-adrenoceptor binding in cerebral cortical membranes without affecting beta-adrenoceptor sites. A selective reduction in alpha 1-adrenoceptors was achieved by injecting yohimbine prior to EEDQ, whereas prazosin pretreatment yielded a selective reduction in alpha 2-adrenoceptor binding. Administration of EEDQ decreased norepinephrine-stimulated inositol phosphate and cyclic adenosine monophosphate (cAMP) accumulation in cerebral cortical tissue as well as the cAMP response to isoproterenol in combination with 6-fluoronorepinephrine without modifying the second messenger response to isoproterenol alone. The results suggest that, under the proper conditions, EEDQ administration can selectively diminish rat brain alpha-adrenoceptor number and function, yielding a procedure that may be useful for defining the behavioral and physiological properties of these sites.

Adrenergic alpha-Antagonists↗
PubMed1989

Glucocorticoid administration increases receptor-mediated and forskolin-stimulated cyclic AMP accumulation in rat brain cerebral cortical slices.

Experiments were undertaken to examine the influence of dexamethasone administration on adrenergic receptor-mediated cAMP accumulation in rat brain cerebral cortical slices. While the initial response to continuous treatment with dexamethasone or ACTH was a decrease in the alpha-adrenergic receptor-mediated augmentation of isoproterenol-stimulated cAMP production, more prolonged administration of these substances also increased beta-adrenergic receptor-stimulated cAMP accumulation. Dose-response studies revealed a dose-dependent increase in beta-adrenergic receptor-stimulated cAMP production. Prolonged administration of either dexamethasone or ACTH also increased 2-chloradenosine-, vasoactive intestinal peptide (VIP)-, and forskolin-stimulated cAMP production in the brain slice. These results, together with previous findings, suggest that glucocorticoids have at least two effects on the brain neurotransmitter receptor-coupled cAMP generating system which may be important for maintaining homeostasis during times of stress.

2-Chloroadenosine↗
PubMed1989

gamma-Aminobutyric acidB receptor activation modifies agonist binding to beta-adrenergic receptors in rat brain cerebral cortex.

The interaction of isoproterenol with beta-adrenergic receptor (beta AR) binding sites was measured in membranes prepared from rat brain cerebral cortical slices previously incubated in the presence or absence of gamma-aminobutyric acid (GABA) receptor agonists. Both GABA and baclofen, but not isoguvacine, altered beta AR agonist binding by increasing the affinity of both the low- and high-affinity binding sites and by increasing the proportion of low-affinity receptors. The response to baclofen was stereoselective, and the effect of GABA was not inhibited by bicuculline. The results suggest that GABAB, but not GABAA, receptor activation modifies the coupling between beta AR and stimulatory guanine nucleotide-binding protein, which may in part explain the ability of baclofen to augment isoproterenol-stimulated cyclic AMP accumulation in brain slices.

Animals↗
PubMed1988

The influence of electroshock on adrenoceptor function in rat brain cerebral cortex: selectivity for the alpha-adrenoceptor site.

The present study was undertaken to examine the effect of electroshock on adrenoceptor-mediated cAMP and inositol phosphate accumulation in rat brain cerebral cortical slices. Under the conditions of these experiments, isoproterenol-induced cAMP accumulation was unaltered by electroshock, although there was a significant reduction in the norepinephrine- and isoproterenol + 6-fluoronorepinephrine-stimulated responses. No change in alpha-adrenoceptor-mediated inositol phosphate accumulation was noted. The results indicate that electroshock selectively modifies an alpha-adrenoceptor system in brain that differs from that associated with inositol phosphate accumulation.

Animals↗
PubMed1988

Augmentation of neurotransmitter receptor-stimulated cyclic AMP accumulation in rat brain: differentiation between the effects of baclofen and phorbol esters.

The augmentation of isoproterenol or vasoactive intestinal peptide (VIP)-stimulated cyclic AMP accumulation in rat brain slices by the GABAB agonist baclofen was compared to that mediated by tumor-promoting phorbol esters. The protein kinase C inhibitor H7 and desensitization of protein kinase C reduced the cyclic AMP augmenting effect of the phorbol ester, but not baclofen. Incubation of brain slices in the presence of both baclofen and a phorbol ester amplified the cyclic AMP response to isoproterenol or VIP to a greater degree than that found with either baclofen or the phorbol ester alone, with the increased augmentation appearing to be additive. These findings indicate that although stimulation of GABAB receptors or protein kinase C activation by phorbol esters have similar effects on transmitter-stimulated cyclic AMP production in brain, these augmenting actions appear to be independently mediated.

Animals↗
PubMed1988

Evidence for pharmacologically distinct subsets of GABAB receptors.

Activation of GABAB receptors augments neurotransmitter-stimulated cyclic AMP accumulation while inhibiting forskolin-mediated second messenger production. Previous studies have revealed that GABAB receptors are associated with a pertussis toxin sensitive G protein, such as Gi. While such a linkage is consistent with the finding that GABAB receptor activation inhibits forskolin-mediated second messenger accumulation, it fails to explain how GABAB agonists are capable of augmenting receptor-mediated cyclic AMP production. The present experiments were undertaken to explore the possible existence of pharmacologically distinct GABAB receptors in an attempt to explain this apparent discrepancy. For the study, a variety of agents were examined for their ability to inhibit GABAB binding to brain membranes and to modify isoproterenol- or forskolin-stimulated second messenger production in rat brain slices. Of the compounds studied, only 3-aminopropylphosphonic acid and 4-aminobutylphosphonic acid were found to inhibit GABAB binding. However, 4-aminobutylphosphonic acid failed to influence either isoproterenol- or forskolin-stimulated cyclic AMP production. On the other hand, while 3-aminopropylphosphonic acid also failed to affect isoproterenol-stimulated second messenger accumulation, it inhibited the forskolin-mediated response. Given this finding, and the fact that some of the agents tested are known to influence GABAB receptor function in other systems, the results indicate a multiplicity of pharmacologically distinct GABAB receptor recognition sites. This discovery paves the way for the development of more selective GABAB receptor agonists and antagonists possessing different therapeutic potentials.

Animals↗
PubMed1987

Selective interaction of tricyclic antidepressants with a subclass of rat brain cholinergic muscarinic receptors.

Experiments were undertaken to determine whether the anticholinergic actions of tricyclic antidepressants are mediated by a selective interaction with a subclass of muscarinic receptors. To this end, the potencies of these antidepressants to inhibit [3H]-QNB binding to rat brain cerebral cortical membranes was compared to their potencies as antagonists of carbachol-stimulated inositol phosphate accumulation in cerebral cortical slices and carbachol-induced inhibition of GTP-stimulated adenylate cyclase in striatal membranes. Whereas amitriptyline was more potent than pirenzepine, a selective muscarinic M1 receptor antagonist, in competing for [3H]-QNB binding sites and as an antagonist of carbachol-induced inhibition of adenylate cyclase, pirenzepine was substantially more active (ten-fold) than amitriptyline in blocking carbachol-stimulated phosphatidyl inositol turnover. Atropine was more potent than all other agents in these assays, failing to display any significant degree of selectivity. The results suggest that the tricyclic antidepressants, in particular amitriptyline, appear to be selective antagonists for muscarinic receptors associated with adenylate cyclase in striatal membranes. Given the current classification of cholinergic receptors, these findings indicate that the tricyclic antidepressants may be useful for defining the properties of M2 receptors in brain.

Adenylyl Cyclase Inhibitors↗