-
[show abstract]
[hide abstract]
ABSTRACT: Nociceptin/orphanin FQ (N/OFQ) peptide and its receptor (NOP) function in the neuromodulation of anxiety, stress and hypothalamic-pituitary-adrenal (HPA) axis activity. We investigated the endogenous NOP system using the selective NOP antagonist, UFP-101, during the HPA axis response to bacterial endotoxin, lipopolysaccharide (LPS). Although i.c.v. N/OFQ (1 microg/rat) had no significant effect on LPS-induced (250 microg/rat i.p) plasma corticosterone release at 30 or 60 min post-i.c.v. injection, i.c.v. UFP-101 (1 microg/rat)/LPS significantly attenuated plasma adrenocorticotrophic hormone and corticosterone at the 30-min time-point compared to i.c.v saline (0.9%)/LPS. Parvocellular paraventricular nucleus (PVN) corticotrophin-releasing factor (CRF) and corticotrophic pro-opiomelanocortin (POMC), but not parvocellular PVN arginine vasopressin (AVP), mRNA expression was significantly increased by LPS compared to non-LPS control. Intracerebroventricular UFP-101/LPS treatment was associated with increased POMC mRNA expression 4 h after injection and a clear trend towards increased parvocellular CRF mRNA. Furthermore, i.c.v. UFP-101 was selectively associated with an LPS-induced increase in parvocellular AVP mRNA, an effect that was absent in the i.c.v saline/LPS group. To determine whether LPS challenge was associated with compensatory changes in N/OFQ precursor or NOP receptor mRNAs, in a separate study, we undertook reverse transcriptase-polymerase chain reaction analysis of preproN/OFQ and NOP transcripts. In support of an endogenous role for central N/OFQ in inflammatory stress, we found that LPS significantly increased preproN/OFQ transcript expression in the hypothalamus 4 h after injection compared to the saline control. No changes in preproN/OFQ mRNA level in the hippocampus or basal forebrain (including bed nucleus of stria terminalis) were seen, albeit at 4 h. LPS was associated with a significant attenuation of NOP mRNA in the basal forebrain at 4 h, possibly as a compensatory response to increased N/OFQ release. Although the exact mechanisms require elucidation, the findings obtained in the present study provide evidence indicating that the endogenous NOP system is involved in the acute HPA axis response to immune challenge.
Journal of Neuroendocrinology 10/2009; 21(11):888-97. · 3.14 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: In addition to the well-established effects of corticotrophin-releasing factor (CRF) synthesized in the hypothalamic paraventricular nucleus in modulating the stress response, CRF has also been implicated in a number of other functions. In particular both pro- and anti-inflammatory effects have been proposed for CRF. In the present study we have investigated the effects of 14 day peripheral infusion of CRF on the development of adjuvant-induced arthritis (AA) in the rat. To avoid confounding effects of the CRF stimulating endogenous corticosterone, all animals in the study were adrenalectomized. We were unable to determine any effect of the treatment at either of the doses of CRF investigated. The bioactivity of the CRF was confirmed in vitro and the presence of substantial circulating levels of CRF in plasma in the high dose group at time of sacrifice suggest that the CRF was successfully infused over the 14 day experimental period. These data suggest that CRF is not important in the mediation of AA. Alternatively either intact adrenal glands may be required for the action of CRF to become apparent or locally produced endogenous CRF may have more subtle effects than chronic infusion of synthetic CRF.
07/2009; 1(2):105-111.
-
[show abstract]
[hide abstract]
ABSTRACT: We have summarised evidence in the literature for modulatory effects of stress on inflammatory autoimmune disease. We find that overall there is strong evidence for such an interrelationship. Apparent discrepancies between groups and studies are probably due to differences in experimental design, whether longitudinal or retrospective. Other important variables are the specific effects of different types of stress and the intensity and timing of the stressor relative to onset of inflammation. We conclude that there is much of benefit to be learned from scientific study of stress, such as harnessing and rationalising of stressful experiences through self-expression in patients, or the identification of novel anti-inflammatory compounds activated by stress.
07/2009; 7(4):261-266.
-
[show abstract]
[hide abstract]
ABSTRACT: We have previously reported that rats exposed chronically to citalopram are able to elicit a corticosterone but not adrenocorticotropic hormone (ACTH) response to restraint stress. Thus we proposed the hypothesis that the corticosterone response to restraint in citalopram-treated rats was maintained due to increased adrenal sensitivity to lower ACTH levels. To test this hypothesis, we intravenously injected ACTH (1-24) to rats (dose 3 ng/rat) exposed to citalopram through minipump infusion for 14 days and to control rats (no citalopram). ACTH significantly increased plasma corticosterone levels in both control and citalopram treated rats over a period of 120 min. There was no significant difference in plasma corticosterone between citalopram treated rats and control rats at any time point. Therefore we conclude that, under these experimental conditions, citalopram does not appear to sensitize the rodent adrenal gland to ACTH, and that other mechanisms may be responsible for the ACTH/corticosterone disconnection.
Journal of Psychopharmacology 12/2007; 21(8):885-7. · 3.04 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The arginine vasopressin (Avp) 1b receptor (Avpr1b) present on anterior pituitary corticotrophs is involved in the stimulation of adrenocorticotrophic hormone (ACTH) secretion, especially during times of stress. Corticotrophin-releasing hormone (CRH) is considered the major ACTH secretagogue during acute stress whereas Avp appears to be the more dominant mediator of the hypothalamic-pituitary-adrenal (HPA) axis response during chronic stress situations. To investigate the role of the Avpr1b in the HPA axis response to acute stress, we measured ACTH and corticosterone (CORT) plasma levels in Avpr1b knockout (KO) mice and wild-type controls in response to bacterial lipopolysaccharide (LPS) challenge and ethanol (EtOH) administration. Mice deficient in Avpr1b had markedly compromised plasma ACTH and CORT responses to acute (30 min) LPS, but normal ACTH and CORT response to more extended exposure (4 h) to the immune system activator. The plasma ACTH and CORT levels stimulated by intoxicating, sedative doses of EtOH (3.2 and 4 g/kg) were significantly decreased in the Avpr1b KO mice compared to wild-type littermates. Significantly higher EtOH-induced plasma ACTH and CORT secretion was measured in female than in male Avpr1b wild-type mice. There were no differences in the blood alcohol levels following acute EtOH administration in Avpr1b KO or wild-type mice of either gender. Our results clearly suggest that Avpr1b plays a significant role in the HPA axis response to acute immune stress and EtOH intoxication.
Journal of Neuroendocrinology 08/2007; 19(7):543-51. · 3.14 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The involvement of nociceptin (N/OFQ) and the nociceptin/orphanin FQ peptide (NOP) receptor in behavior associated with stress and anxiety has been established but their role in the regulation of the hypothalamo-pituitary-adrenal (HPA) axis under conditions of stress has not been fully investigated. We used the selective NOP receptor antagonist UFP-101 to examine the contribution of endogenous N/OFQ to HPA axis control under conditions of restraint stress in the morning and the evening. We found that in the morning during the HPA axis circadian nadir rats exposed to restraint stress in both the presence and absence of UFP-101 exhibited significantly elevated plasma corticosterone at 30 min post-i.c.v. injection compared to the home cage control group. Additionally, rats treated with UFP-101 and exposed to restraint had significantly elevated corticosterone levels at 60 min post-i.c.v. injection compared to all other treatment groups. Interestingly, while there was a significant increase in the expression of CRF mRNA in the paraventricular nucleus (PVN) of rats exposed to restraint stress only, there was no comparable increase in those co-treated with UFP-101. There was no change in the expression of AVP or POMC mRNA in any of the treatment groups. In contrast, when carried out in the evening we observed significantly elevated plasma corticosterone in the vehicle-treated restraint group only at 30 min post-i.c.v. injection. There was no significant difference between the UFP-101-treated restraint group and either of the home cage control groups or the vehicle-treated restraint group. Additionally, in contrast to the morning study, UFP-101 did not prolong glucocorticoid release at the 60 min time-point. These results demonstrate for the first time a differential effect of UFP-101 on restraint stress-induced HPA axis activity characterized by significant prolongation of stress-induced activity in the morning but no significant effect on the response to restraint in the evening.
Neuroscience 08/2007; 147(3):757-64. · 3.38 Impact Factor
-
Annals of the New York Academy of Sciences 12/2006; 771(1):449 - 458. · 3.15 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: We have previously demonstrated that Gram-negative bacterial endotoxin can exert long-term protective effects against the chronic inflammatory disease adjuvant arthritis in rats. The present study was designed to investigate the mechanisms and time-course of hypothalamo-pituitary-adrenocortical (HPA) axis activity and cytokine secretion underlying this phenomenon. Rats were injected with endotoxin (lipopolysaccharide) and blood was collected either 7 or 21 days later. Priming with endotoxin induced a biphasic alteration in secretion of adrenocorticotrophic hormone and corticosterone in response to a second injection of endotoxin, with decreased secretion observed after 7 days whereas robust secretion was observed at 21 days. Seven days following priming with endotoxin, plasma concentrations of pro-inflammatory cytokines interleukin (IL)-6 and interferon (IFN)-gamma were reduced by 90%, and tumour necrosis factor (TNF)-alpha by 70%, compared to saline-treated rats, whereas robust secretion of the anti-inflammatory cytokine IL-10 was maintained in both groups. A similar net change favouring an anti-inflammatory cytokine secretory milieu was also observed 21 days following priming with endotoxin. This study provides evidence that the long-term protective effects of endotoxin on inflammation are associated with a sustained reduction in secretion of pro-inflammatory cytokines. HPA axis hypoactivity at 7 days suggests that corticosterone is not involved in suppressing IL-6, IFN-gamma and TNF-alpha at this time point. Conversely, hypersecretion of corticosterone at 21 days may underlie synchronous suppression of IL-6 and IFN-gamma. These data provide novel insight into interactions between HPA axis activity and cytokine secretion following endotoxin priming prior to induction of inflammatory disease.
Journal of Neuroendocrinology 12/2006; 18(11):875-82. · 3.14 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Nociceptin/orphanin FQ (N/OFQ) is an opioid-related peptide that stimulates corticosterone release after i.c.v. administration in non-stressed rats. We employed in situ hybridization histochemistry to investigate N/OFQ-stimulated activation of the HPA axis at the hypothalamic and pituitary level. We have demonstrated that N/OFQ-induced activation of the HPA axis is mediated via the central N/OFQ peptide receptor (NOP) using the recently described selective NOP antagonist [Nphe(1),Arg(14),Lys(15)]nociceptin/orphanin FQ-NH(2) (UFP-101). We found that, at 30 min post-i.c.v. injection, N/OFQ dose-dependently increased plasma adrenocorticotrophin hormone and corticosterone compared with the vehicle-injected controls. N/OFQ (1.0 microg) significantly increased CRF mRNA but not AVP mRNA within the parvocellular hypothalamic paraventricular nucleus compared with the control group, and significantly increased pro-opiomelanocortin (POMC) mRNA in the anterior pituitary. While UFP-101 (1.0 microg) alone had no significant effect on plasma corticosterone concentration it blocked the effect of N/OFQ (1.0 microg) on plasma corticosterone levels when compared with N/OFQ administered alone. UFP-101 also blocked the N/OFQ-induced increase in CRF mRNA and POMC mRNA. These results demonstrate that centrally administered N/OFQ activates the HPA axis via up-regulation of CRF and POMC mRNA and stimulation of corticosterone release in rats. Further, we have demonstrated for the first time that the selective NOP receptor antagonist UFP-101 blocks these effects indicating that N/OFQ-induced HPA axis activation is mediated via central NOP receptors.
Neuroscience 10/2006; 141(4):2051-7. · 3.38 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The release of endogenous glucocorticoids is critical in regulating the severity of disease activity in patients with inflammatory conditions such as rheumatoid arthritis (RA). Blocking cortisol production results in a flare-up in disease activity in RA patients, and surgical removal of the adrenals in patients with Cushing's disease has been reported to exacerbate autoimmune disease. In adjuvant-induced arthritis (AA; a rat model of RA), there is an activation of the hypothalamo-pituitary-adrenal (HPA) axis associated with the development of inflammation. In addition, there are profound changes in peptides within the paraventricular nucleus, which are responsible for regulating the HPA axis. These changes have profound implications on the ability of AA rats to respond to acute stress. Understanding the regulation of the HPA axis in health and disease holds out the promise of targeted therapy to alleviate inflammatory conditions. This article will consider the impact of stress on an individual and his or her susceptibility to inflammation. We wish to question the idea that stress is "all bad." As we shall see, exposure to a single acute stressor can alter the phenotype of the rat to change it from being susceptible to resistant in autoimmune disease models. This alteration in susceptibility takes days to manifest itself, but can last for weeks, suggesting beneficial effects of exposure to an acute stressor.
Annals of the New York Academy of Sciences 07/2006; 1069:51-61. · 3.15 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) stress axis and disturbances in serotonin (5-HT) neurotransmission have been implicated in the pathogenesis of depressive disorder. Repeated social defeat of male NMRI mice has been shown to induce increases in core body temperature and corticosterone, indicative of a state of chronic stress in subordinate animals. The present study further characterised the HPA axis response to social defeat stress, and also examined hippocampal extracellular 5-HT release during the stress. Exposure to an acute social defeat elicits increases in plasma adrenocorticotrophic hormone and corticosterone levels, peaking at 15 and 30 min, respectively, and enhances corticotrophin-releasing factor (CRF) mRNA, but not arginine vasopressin (AVP) mRNA within the medial parvocellular division of the hypothalamic paraventricular nucleus. A concomitant increase in hippocampal corticosterone and 5-HT levels is observed. By contrast, although chronic social defeat is associated with greatly elevated corticosterone levels, the predominant drive appears to be via parvocellular AVP rather than CRF. Furthermore, subordinate animals allowed to recover for 9 days after chronic social defeat display an increase in immobility in the forced swimming model of depression, indicating that animals previously exposed to the homotypic defeat stress are sensitised to the behavioural effects of a novel stressor. These results demonstrate that social defeat induces prolonged activation of the HPA axis and alterations in 5-HT neurotransmission that could be of relevance to some of the pathological abnormalities observed in clinical depression.
Journal of Neuroendocrinology 06/2006; 18(5):330-8. · 3.14 Impact Factor
-
Rheumatology 03/2006; 45(2):229-30. · 4.06 Impact Factor
-
Rheumatology 10/2005; 44(9):1097-100. · 4.06 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Serotonin re-uptake inhibitors (SSRIs) can affect the basal activity of the hypothalamic-pituitary-adrenal (HPA) axis in rats. A single injection of citalopram has been shown to stimulate the HPA axis while repeated administration leads to attenuation of the corticosterone response to the SSRI. The purpose of this work was to investigate the rodent HPA axis response to restraint stress, following acute and chronic treatment with the SSRI citalopram. We have demonstrated that a single injection of citalopram is able to prolong acute restraint-induced increases in plasma levels of corticosterone and adrenocorticotrophin (ACTH). This is possibly mediated by arginine vasopressin (AVP) in the parvocellular cells of the paraventricular nucleus (pPVN), as treatment with citalopram or restraint alone did not increase AVP mRNA in pPVN while the combination of treatments resulted in a significant increase in AVP mRNA in the pPVN. In contrast, the increase in corticotrophin-releasing factor (CRF) mRNA in the pPVN in response to acute restraint stress was not altered by citalopram. Oxytocin (OT) mRNA was also increased in the magnocellular PVN (mPVN) by the solo treatments of citalopram and restraint, and was not further enhanced by the dual treatment of restraint and citalopram. Chronic treatment with citalopram did not alter basal plasma levels of corticosterone or ACTH. However, the ACTH response to acute restraint was attenuated following chronic citalopram treatment. AVP mRNA in the pPVN was significantly elevated in response to chronic citalopram compared with saline controls suggesting an effect mediated through the AVP subset of pPVN neurones. The CRF mRNA response to acute restraint was not altered in rats treated chronically with citalopram. OT mRNA was not enhanced in the mPVN following chronic infusion of citalopram but was increased by acute restraint stress. We conclude from these data that both acute and chronic citalopram treatment has the potential to alter the rodent response to acute restraint stress. These effects appear to be regulated by the AVP-containing subset of CRF neurons in the pPVN and thus suggest that parvocellular AVP may have an important role in mediating the actions of SSRIs.
Journal of Endocrinology 07/2005; 185(3):373-82. · 3.55 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: We have summarised evidence in the literature for modulatory effects of stress on inflammatory autoimmune disease. We find that overall there is strong evidence for such an interrelationship. Apparent discrepancies between groups and studies are probably due to differences in experimental design, whether longitudinal or retrospective. Other important variables are the specific effects of different types of stress and the intensity and timing of the stressor relative to onset of inflammation. We conclude that there is much of benefit to be learned from scientific study of stress, such as harnessing and rationalising of stressful experiences through self-expression in patients, or the identification of novel anti-inflammatory compounds activated by stress.
Stress 01/2005; 7(4):261-6. · 2.48 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Enhanced corticosterone release by female compared to male rats under basal and stress conditions is well documented. The demonstration that gonadectomy enhances stress-induced corticosterone secretion in male rats, but reduces such levels in female rats, suggests a causal association between gonadal steroids and corticosterone release. The present study examined the corticosterone profile of sham gonadectomized and gonadectomized female and male rats under basal and stress conditions. An automated sampling system collected blood from each freely moving, unanaesthetized rat every 10 min (i) over a 24-h period; (ii) following noise stress; and (iii) following an immune-mediated stress (lipopolysaccharide, LPS). Plasma was analysed for corticosterone content using radioimmunoassay. Castration resulted in a significant increase in basal corticosterone release compared to the sham-castrated male rats. Pulsar analysis revealed a significant two-fold increase in the number of corticosterone pulses over 24 h. Corticosterone increases in response to noise stress and to LPS injection were enhanced following castration. Conversely, ovariectomy resulted in a two-fold reduction in the number of corticosterone pulses as well as the stress response compared to sham-ovariectomized female rats. Arginine vasopressin (AVP), corticotrophin-releasing hormone (CRH) and glucocorticoid receptor mRNAs in the paraventricular nucleus and pro-opiomelanocortin (POMC) mRNA in the anterior pituitary were analysed post-LPS administration by in situ hybridization. Significantly higher values were found for AVP, CRH and POMC mRNAs examined for sham females and castrated males compared to sham males and ovariectomized females. This study confirms previous reports concerning the influence of gonadal factors in regulating HPA axis activity and stress responsiveness. The present results extend these observations to the regulation of the dynamic pattern of corticosterone release under basal conditions and suggests that this alteration in pulsatility is important for the differences in stress responsiveness when comparing males and females.
Journal of Neuroendocrinology 07/2004; 16(6):516-24. · 3.14 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Endomorphin 1 (EM-1) and EM-2 have been widely reported in the cells of the central nervous system (CNS) but limited research has been done regarding their distribution in the peripheral system. The occurrence of EM-1 and -2 in the spleen as measured by RIA and their ability to mediate immune function imply a role for EMs in this area. The current study examines the localization of EM-1 and -2 in the immune cells of the spleen of male and female rats via an immunohistochemical procedure. In both genders, EM-1 and -2 immunoreactive staining was predominantly present in macrophages and B cells with minimal EM immunoreactive staining in T cells. This is the first evidence of a differential distribution of EM-1 and -2 in cells of the immune system.
Peptides 02/2004; 25(1):91-4. · 2.43 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) are expressed in cells of the immune system where they exert immunomodulatory roles, but these neuropeptides are poorly characterized in human immune tissues. The aim of this study was to determine concentrations and distribution of CRH and AVP in nonactivated human peripheral blood mononuclear cells (PBMC). PBMC from normal human subjects were separated into enriched subpopulations of T and B cells and monocytes/macrophages by a magnetic bead/monoclonal antibody technique. CRH and AVP were measured in cell extracts by radioimmunoassay (RIA). CRH-immunoreactivity (ir) ranged 0.24-0.8 fmol/million cells (n = 6 subjects) in T cell extracts, 0.4-2.7 fmol/million cells (n = 4) in B cells and 0.63-2.16 fmol/million cells (n = 4) in macrophages. AVP-ir ranged 0.2-0.95 fmol/million cells in T cell extracts, <0.1-0.8 fmol/million cells in B cells and 0.14-3.19 fmol/million cells in macrophages. Reversed-phase high-performance liquid chromatography (HPLC) of T and B cell extracts revealed a peak of CRH-ir which coeluted with synthetic CRH-41; this peak was not present in macrophages. A second peak of CRH-ir which eluted in a more hydrophobic position was observed in extracts of T and B cells and macrophages. This unidentified form of CRH-ir is the predominant form of CRH-ir in nonactivated human PBMC. This is the first study to demonstrate that CRH-ir and AVP-ir are colocalized within human T cells, B cells and monocytes/macrophages. We have confirmed observations of a variant form of CRH-ir in human PBMC and show that this is the predominant form in macrophages and B cells whereas CRH-ir, which coelutes with CRH(1-41) on HPLC, is present in significant amounts only in T cells. These data also confirm that CRH-ir in human PBMC is not urocortin because the antiserum used in the CRH RIA does not bind to urocortin.
Journal of Neuroendocrinology 12/2003; 15(11):1070-4. · 3.14 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: A defective hypothalamo-pituitary-adrenal axis response to inflammatory cytokines may contribute to the pathophysiology of rheumatoid arthritis (RA). The purpose of this study was to define further the mechanisms responsible for this dysregulation. Six normal individuals and seven patients with active RA were recruited and given an oral dose of dexamethasone at 2300 h the evening before the study. The next day, an i.v. catheter was fitted at 1300 h. Blood samples were collected between 1400 h and 1700 h before and after infusion (at 1500 h) of corticotrophin releasing factor (CRF). Plasma was separated and stored at-20 degrees C before radioimmunoassay for ACTH, cortisol and dihydroepiandrosterone (DHEA). Before the CRF challenge, ACTH and cortisol were significantly increased and DHEA significantly decreased in the patients with RA compared with the controls. Neither ACTH nor DHEA was significantly altered after CRF infusion. Control individuals did not mount a cortisol response to infusion of CRF. Similarly, four of the patients with RA did not respond to CRF. However, in contrast to the controls, three of the patients mounted an immediate and sustained cortisol response after receiving CRF. These data reveal that three of the seven patients with RA were able to escape from dexamethasone suppression and mount a cortisol response to CRF challenge. This suggests that there may be a subpopulation of patients with RA who have impaired glucocorticoid feedback. The implications of this alteration for disease progression remain to be determined.
Journal of Endocrinology 08/2003; 178(1):55-60. · 3.55 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The aim of this study was to investigate imidazoline(2) (I(2)) binding site- and alpha(2)-adrenoceptor-mediated control of central noradrenergic and HPA axis activity in control rats and chronically stressed rats with adjuvant-induced arthritis (AA). Basal levels of extracellular nonadrenaline (NA) in the region of the hypothalamic paraventricular nucleus (PVN) of AA rats were significantly greater than controls. Both the I(2) binding site selective ligand BU224 (10 mg kg(-1) i.p.) and the alpha(2)-adrenoceptor antagonist RX821002 (2.5 mg kg(-1) i.p.) significantly elevated extracellular levels of NA in the PVN region and plasma corticosterone (CORT) in a rapid and transient manner in both control and AA rats. The noradrenergic response of AA rats to BU224 was significantly enhanced compared with drug treated controls. There was a significant correlation between extracellular NA in the PVN region and plasma CORT following BU224 and RX821002. In conclusion, central noradrenergic and HPA axis activity in control and chronically stressed AA rats appear to be under the control of both I(2) binding sites and alpha(2)-adrenoceptors. Increased basal levels of extracellular NA in the PVN region of AA rats suggests increased noradrenergic activity in these animals which is modulated to a greater extent by I(2) binding sites than by alpha(2)-adrenoceptors.
Neuropharmacology 07/2002; 42(7):958-65. · 4.81 Impact Factor
