Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.1 (adenylate cyclase)
 19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Opioids have been thought to induce analgesia by activating the descending pain control system, especially at the level of periaqueductal gray, and regulate the neurotransmitter release through the inhibition of calcium channel. In the present study, the modulatory effects of protein kinase C and protein kinase A on the mu-opioid agonist-induced inhibition of the high-voltage activated calcium current were examined in the acutely dissociated rat periaqueductal gray neurons with the nystatin-perforated patch-clamp technique. Among 505 neurons tested, the barium current passing through the high-voltage activated calcium channels of 172 neurons (34%) were inhibited by 32+/-3% with the application of an mu-opioid agonist, [D-Ala(2),N-MePhe(4),Gly(5)-ol]-enkephalin (DAMGO, 1 microM). The barium currents itself and the DAMGO-induced inhibitory effects were not affected by the application of either an adenylate cyclase activator (forskolin, 1 microM) or a protein kinase inhibitor (staurosporin, 10 nM) for 2 min. The DAMGO inhibition was completely and irreversibly antagonized by the application of a protein kinase C activator, phorbol-12-myristate-13-acetate (PMA, 1 microM) for 2 min without any alteration of the barium current itself. However, the antagonizing effect of PMA was completely abolished by the application of 10 nM staurosporin for 2 min. After then, PMA did not show the antagonizing effect any more. Inversely, when staurosporin was applied before PMA, the antagonizing effect of PMA was also not shown. These results demonstrate that the mu-opioid agonist-induced inhibition of the periaqueductal gray neuronal high-voltage activated calcium current can be antagonized by protein kinase C activation. This finding may provide us a significant clue to understand the action mechanism of opioid-induced analgesia in the periaqueductal gray.
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PMID:Antagonizing effect of protein kinase C activation on the mu-opioid agonist-induced inhibition of high voltage-activated calcium current in rat periaqueductal gray neuron. 1159 91

Stimulation of the brain CCK2 receptor by the C-terminal octapeptide CCK8 of cholecystokinin (CCK) negatively modulates opioid responses. This suggests the existence of physiologically relevant interactions between endogenous CCK and opioid peptides, opening new perspectives particularly in the treatment of pain or drug addiction. CCK2 receptor-deficient mice were used to analyze the incidence of this gene invalidation on opioid system. Compared with wild-type mice, mutants exhibited the following: (1) a hypersensitivity to the locomotor activity induced by inhibitors of enkephalin catabolism or by morphine; (2) a spontaneous hyperalgesia to thermal nociceptive stimulus, which was reversed by previous administration of the NMDA antagonist MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10-imine maleate], and a large reduction in analgesic effects of endogenous or exogenous opioids; and (3) a more severe withdrawal syndrome after chronic morphine treatment. As expected, stimulation of mu, delta, and D2 receptors on brain tissue of wild-type animals induced a dose-dependent decrease in adenylate cyclase activity, whereas a striking mirror effect was observed in mutants. All of these results suggest that the absence, in knock-out mice, of the negative feedback control on the opioid system, normally performed out by CCK2 receptor stimulation, results in an upregulation of this system. These biochemical and pharmacological results demonstrate the critical role played by CCK2 receptors in opioid-dependent responses.
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PMID:Deletion of CCK2 receptor in mice results in an upregulation of the endogenous opioid system. 1188 May 31

Pain and hyperalgesia from deep somatic tissue (i.e., muscle and joint) are processed differently from that from skin. This study examined differences between deep and cutaneous tissue allodynia and the role of cAMP in associated behavioral changes. Capsaicin was injected into the plantar aspect of the skin, plantar muscles of the paw, or ankle joint, and responses to mechanical and heat stimuli were assessed until allodynia resolved. Capsaicin injected into skin resulted in a secondary mechanical allodynia and heat hypoalgesia lasting approximately 3 hr. In contrast, capsaicin injection into muscle or joint resulted in a long-lasting bilateral (1-4 weeks) mechanical allodynia with a simultaneous unilateral heat hypoalgesia. The pattern and degree of inflammation were similar when capsaicin was injected into skin, muscle, or joint, with peak increases 24 hr after injection. Heat hypoalgesia that occurs after injection into deep tissue was reversed by spinal blockade of adenylate cyclase or protein kinase A (PKA). Interestingly, mechanical allodynia was reversed if adenylate cyclase or PKA inhibitors were administered spinally 24 hr, but not 1 week, after injection of capsaicin. Spinally administered 8-bromo-cAMP resulted in a similar pattern, with heat hypoalgesia and mechanical allodynia occurring simultaneously. Thus, injection of capsaicin into deep tissues results in a longer-lasting mechanical allodynia and heat hypoalgesia compared with injection of capsaicin into skin. The mechanical allodynia depends on early activation of the cAMP pathway during the first 24 hr but is independent of the cAMP pathway by 1 week after injection of capsaicin.
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PMID:Stimulation of deep somatic tissue with capsaicin produces long-lasting mechanical allodynia and heat hypoalgesia that depends on early activation of the cAMP pathway. 1209 20

A peptide termed nociceptin/orphanin FQ (N/OFQ) was recently identified as an endogenous agonist for the opioid receptor-like receptor currently specified as NOP receptor. Despite many structural homologies to the opioid system, the NOP receptor shows low-affinity binding to selective opioid agonists or antagonists. Vice versa, N/OFQ selectively activates the NOP receptor but not any opioid receptor subtype. This novel receptor/ligand system is widely expressed in the brain. At the cellular level, the actions of N/OFQ resemble those elicited by opioid peptides. The NOP receptor is coupled to G-proteins, whose activation results in inhibition of adenylate cyclase, modulation of calcium and potassium conductances, and regulation of transmitter systems. At the behavioral level, systemic application of N/OFQ elicits a unique range of responses, including a wide range of effects on pain processing such as hyperalgesia, analgesia, and allodynia, as well as anxiolytic actions, modulation of opioid-mediated processes, and influences on learning and memory.
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PMID:Nociceptin/orphanin FQ: actions within the brain. 1270 19

Petasites hybridus is used in Chinese herbal medicine. S-petasin is a bioactive compound isolated from leaves or roots of Petasites hybridus. S-petasin has been used to relieve gastrointestinal pain, lung disease, and spasms of the urogenital tract. However, the side effect of S-petasin on endocrine systems are still not clear. This study explored the effects of S-petasin on the release of corticosterone in vivo and in vitro. An intravenous injection of S-petasin (10 microg/kg) decreased both basal and adrenocorticotropin (ACTH)-induced plasma corticosterone concentration in male rats. In vitro, S-petasin (3 x 10(-6) - 10(-4) M) caused a significant reduction of basal and ACTH-stimulated release of corticosterone from the enzymatically dispersed rat zona fasciculata-reticularis (ZFR) cells in a dose-dependent manner. In order to study possible mechanisms, ZFR cells were incubated with S-petasin (10(-5) M) in the presence or absence of forskolin (adenylate cyclase activator, 10(-6) - 10(-4) M), 8-Br-cAMP (a cAMP analogue, 10(-6) 10(-4) M), 25-OH-cholesterol (pregnenolone biosynthesis precursor, 10(-5) M) combined with trilostane (a blocker of 3beta-hydroxysteriod dehydrogenase, 3beta-HSD, 10(-6) M) and deoxycorticosterone (corticosterone biosynthesis precursor, 10(-9) - 10(-6) M) at 37 degrees C for 1h. The concentration of pregnenolone and corticosterone in media were measured by radioimmunoassay. The stimulatory effects of corticosterone secretion induced by forskolin (10(-5) - 10(-4) M), 8-Br-cAMP (10(-5) - 10(-4) M) and deoxycorticosterone (10(-7) - 10(-6) M) were reduced by S-petasin at 10(-5) M. The stimulatory effects of pregnenolone secretion induced by 25-OH-cholesterol combined with or without trilostane was reduced by S-petasin at 10(-5) M. These results suggest that S-petasin inhibits the production of corticosterone from rat ZFR cells in part through decreasing the activities of adenylyl cyclase, P450scc and 11beta-hydroxylase.
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PMID:Effects of S-petasin on corticosterone release in rats. 1281 4

Proinflammatory prostaglandin E2 is known to sensitize sensory neurons to noxious stimuli. This sensitization is mediated by the cAMP-dependent protein kinase (PKA) signal pathway. The capsaicin receptor TRPV1, a non-selective cation channel of sensory neurons involved in the sensation of inflammatory pain, is a target of PKA-mediated phosphorylation. Our goal was to investigate the influence of PKA on Ca(2+)-dependent desensitization of capsaicin-activated currents. By using site-directed mutagenesis, we created point mutations at PKA consensus sites and studied wild-type and mutant channels transiently expressed in HEK293t cells under whole-cell voltage clamp. We found that forskolin, a stimulator of adenylate cyclase, decreased desensitization of TRPV1. The selective PKA inhibitor H89 inhibited this effect. Mimicking phosphorylation at PKA consensus sites by replacing Ser-6, Ser-116, Thr-144, Thr-370, Ser-502, Ser-774, or Ser-820 with aspartate resulted in five mutations (S116D, T144D, T370D, S774D, and S820D) that exhibited decreased desensitization as well. However, disrupting phosphorylation by replacing respective sites with alanine resulted in four mutations (S6A, T144A, T370A, and S820A) with desensitization properties resembling those of the aspartate mutations. Significant changes in relative permeabilities for Ca2+ over Na+ or in capsaicin sensitivity could not explain changes in desensitization properties of mutant channels. In mutations S116A, S116D, T370A, and T370D, pretreatment of cells with forskolin did not reduce desensitization as compared with wild-type and other mutant channels. We conclude that Ser-116 and possibly Thr-370 are the most important residues involved in the mechanism of PKA-dependent reduction of desensitization of capsaicin-activated currents.
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PMID:Desensitization of capsaicin-activated currents in the vanilloid receptor TRPV1 is decreased by the cyclic AMP-dependent protein kinase pathway. 1450 58

In persistent pain, the spinal cord concentration of the opioid peptide dynorphin increases dramatically, yet the function of dynorphin remains unknown. If prodynorphin expression could be manipulated in vivo, it might be possible to determine what role dynorphin plays in persistent pain. Previous work in our laboratory showed that prodynorphin expression is regulated through the cyclic adenosine monophosphate pathway. Therefore, we attempted to enhance prodynorphin expression in the spinal cord of rats by stimulating adenylate cyclase with cholera toxin; however, contrary to our hypothesis, intrathecally administered cholera toxin did not enhance prodynorphin expression. Rather, cholera toxin suppressed the increase in prodynorphin produced by inflammation. Cholera toxin also inhibited the allodynia and hyperalgesia associated with inflammation and nerve injury. Interestingly, the antiallodynic and antihyperalgesic actions of cholera toxin were reversed with the opioid receptor antagonist, naloxone. These findings suggest that cholera toxin enhances or unmasks an endogenous opioid pathway to produce its antiallodynic and antihyperalgesic effects. Furthermore, these data indicate that the suppression of the inflammation-induced increase in spinal cord prodynorphin is caused by the opioid-mediated decrease in the nociceptive stimulus.
J Pain 2001 Apr
PMID:Intrathecally administered cholera toxin blocks allodynia and hyperalgesia in persistent pain models. 1462 33

The 5-HT5A receptor is a seven-transmembrane receptor negatively coupled to adenylate cyclase, whose activation opens K+ channels. The 5-HT5A receptor may thus exert an inhibitory effect on neuronal activity. However, the function of this receptor is still largely unknown, in particular at the spinal level, and this is partly due to lack of specific ligands. Immunocytochemistry using specific anti-5-HT5A antibodies reveals a particularly dense labeling in the two superficial layers of the dorsal horn, suggesting that the 5-HT5A receptor may be involved in the spinal modulation of pain. In addition, a very intense staining in the lumbar dorsolateral nucleus (Onuf nucleus) in both males and females suggests that the 5-HT5A receptor is also involved in micturition through the control of urethral sphincter muscles. Colchicine pretreatment allows the staining of numerous cell bodies in lamina II. Fewer labeled cell bodies are seen in laminae I and III-VI, in the lateral spinal nucleus, and in lamina X. Electron microscope examination of 5-HT5A receptor immunoreactivity in spinal cords from untreated animals confirmed the postsynaptic labeling in all regions studied (dorsal horn, dorsolateral nucleus, and lamina X). The morphological heterogeneity of labeled dorsal horn cell bodies suggests that they belong to functionally distinct neurons (projection neurons and interneurons). In the lumbar dorsolateral nucleus, the labeling is preferentially localized on dendrites, suggesting that in this nucleus 5-HT preferentially acts at the dendritic level. Finally, the dense labeling of postsynaptic specializations suggests that the receptor may be in stock before being addressed to the synaptic differentiation.
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PMID:5-HT5A receptor localization in the rat spinal cord suggests a role in nociception and control of pelvic floor musculature. 1528 7

Studies concerning drugs of abuse have made major contributions in defining the circuitry, as well as cellular and molecular substrates that underlie certain behaviors. Opiate drugs for example, have revealed important insights concerning pain perception and reward. Up to the late 1960s, opiate drugs were suspected to work by mysteriously perturbing lipid membrane structure. We now know the following: the sequence and neuroanatomy of the G-protein coupled receptors that mediate opiate effects; that many proteins interact with opioid receptors such as G-protein sub-unit combinations, G-protein receptor kinases, arrestins and calmodulin; that many signaling molecules are modulated by opioid receptors, including ion channels, kinase cascades and adenyl cyclase. More than 20 different peptides, excised from three precursor proteins by specific proteases, have been shown to be endogenous ligands for opioid receptors. Revealing the molecules of the endogenous opioid system has inspired efforts for developing new opioid analgesics with the hope of minimizing abuse potential. This article will detail the current rationale for searching for less-addictive opiate analgesics and speculate on the future of drug abuse research in furthering our understanding of neural plasticity and the underpinnings of addictive behavior.
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PMID:Secrets of the opium poppy revealed. 1546 45

The therapeutic use of cannabinoids, the components of cannabis sativa L., was investigated in numerous researches in detail. Animal studies revealed that cannabinoid receptor agonists alter pain-associated behaviour, have immune-suppressive properties, suppress tumor growth, modulate sensitisation processes and influence memory and learning. Those effects are mediated by two membrane-bound cannabinoid receptors and as mechanisms of signal transduction blockade of ion channels, inhibition of adenylate cyclase and retrograde inhibition of neurotransmitter release are currently being discussed. In clinical studies oral administration of cannabinoids indicated beneficial results during the therapy of multiple sclerosis, weight loss, nausea and vomiting due to chemotherapy, and intractable pruritus. However, therapy of chronic pain conditions revealed conflicting results and unequivocal success could not have been delivered due to unwanted side effects. Further multicentre studies are required to estimate cannabinoids as novel therapeutic tools for the treatment of chronic pain.
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PMID:[Cannabinoids--signal transduction and mode of action]. 1554 20


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