Girolamo Calo

Bio: Girolamo Calo is an academic researcher from University of Ferrara. The author has contributed to research in topics: Nociceptin receptor & NOP. The author has an hindex of 53, co-authored 304 publications receiving 10148 citations. Previous affiliations of Girolamo Calo include National Institutes of Health.

Pharmacology of nociceptin and its receptor: a novel therapeutic target

Abstract: Nociceptin (NC), alias Orphanin FQ, has been recently identified as the endogenous ligand of the opioid receptor-like 1 receptor (OP4). This new NC/OP4 receptor system belongs to the opioid family and has been characterized pharmacologically with functional and binding assays on native (mouse, rat, guinea-pig) and recombinant (human) receptors, by using specific and selective agonists (NC, NC(1–13)NH2) and a pure and competitive antagonist, [Nphe1]NC(1–13)NH2. The similar order of potency of agonists and affinity values of the antagonist indicate that the same receptor is present in the four species. OP4 is expressed in neurons, where it reduces activation of adenylyl cyclase and Ca2+ channels while activating K+ channels in a manner similar to opioids. In this way, OP4 mediates inhibitory effects in the autonomic nervous system, but its activities in the central nervous system can be either similar or opposite to those of opioids. In vivo experiments have demonstrated that NC modulates a variety of biological functions ranging from nociception to food intake, from memory processes to cardiovascular and renal functions, from spontaneous locomotor activity to gastrointestinal motility, from anxiety to the control of neurotransmitter release at peripheral and central sites. These actions have been demonstrated using NC and various pharmacological tools, as antisense oligonucleotides targeting OP4 or the peptide precursor genes, antibodies against NC, an OP4 receptor selective antagonist and with data obtained from animals in which the receptor or the peptide precursor genes were knocked out. These new advances have contributed to better understanding of the pathophysiological role of the NC/OP4 system, and ultimately will help to identify the therapeutic potential of new OP4 receptor ligands.

Structure of the nociceptin/orphanin FQ receptor in complex with a peptide mimetic.

Abstract: Members of the opioid receptor family of G-protein-coupled receptors (GPCRs) are found throughout the peripheral and central nervous system, where they have key roles in nociception and analgesia. Unlike the 'classical' opioid receptors, δ, κ and μ (δ-OR, κ-OR and μ-OR), which were delineated by pharmacological criteria in the 1970s and 1980s, the nociceptin/orphanin FQ (N/OFQ) peptide receptor (NOP, also known as ORL-1) was discovered relatively recently by molecular cloning and characterization of an orphan GPCR. Although it shares high sequence similarity with classical opioid GPCR subtypes (∼60%), NOP has a markedly distinct pharmacology, featuring activation by the endogenous peptide N/OFQ, and unique selectivity for exogenous ligands. Here we report the crystal structure of human NOP, solved in complex with the peptide mimetic antagonist compound-24 (C-24) (ref. 4), revealing atomic details of ligand-receptor recognition and selectivity. Compound-24 mimics the first four amino-terminal residues of the NOP-selective peptide antagonist UFP-101, a close derivative of N/OFQ, and provides important clues to the binding of these peptides. The X-ray structure also shows substantial conformational differences in the pocket regions between NOP and the classical opioid receptors κ (ref. 5) and μ (ref. 6), and these are probably due to a small number of residues that vary between these receptors. The NOP-compound-24 structure explains the divergent selectivity profile of NOP and provides a new structural template for the design of NOP ligands.

A new selective antagonist of the nociceptin receptor

Abstract: [Phe1Ψ(CH2-NH)Gly2]NC(1-13)NH2 has been tested in the electrically stimulated guinea pig ileum and mouse vas deferens, two nociceptin sensitive preparations. The new compound showed per se little or no effect in the two tissues, but it displaced to the right the concentration-response curves of nociceptin in a concentration-dependent manner. Schild analyses of the data indicated a competitive type of antagonism and pA2 values of 7.02 and 6.75 in the guinea-pig ileum and the mouse vas deferens, respectively. At 10 μM [Phe1Ψ(CH2-NH)Gly2]NC(1-13)NH2 does not modify either the inhibitory effect of deltorphin I (the selective δ opioid receptor agonist) in the mouse vas deferens or that of dermorphine (the selective μ opioid receptor agonist) in the guinea-pig ileum. The present findings indicate that [Phe1Ψ(CH2-NH)Gly2]NC(1-13)NH2 is a selective antagonist of the nociceptin receptor. British Journal of Pharmacology (1998) 123, 163–165; doi:10.1038/sj.bjp.0701640

Address and message sequences for the nociceptin receptor: a structure-activity study of nociceptin-(1-13)-peptide amide.

Abstract: Nociceptin (NC) and some of its fragments as well as nociceptin-(1-13)-peptide amide [NC- (1-13)-NH2] and a series of its analogues were prepared and tested in the mouse vas deferens in an attempt to identify the sequences involved in the activation (message) and in the binding (address) of nociceptin to its receptor. The NC receptor that inhibits the electrically evoked twitches of the mouse vas deferens was demonstrated to be distinct from the delta opioid receptor, since naloxone and Dmt-Tic-OH (a selective delta opioid receptor antagonist) block the delta opioid receptor but have no effect on the nociceptin receptor. Results from structure-activity experiments suggest that (a) the entire sequence of NC may not be required for full biological activities, since NC(1-13)-NH2 is as active as NC; (b) fragments of NC have however to be amidated as in NC(1-13)-NH2 in order to be protected from degradation by proteases; (c) cationic residues (as Arg8,12, Lys9,13) appear to play a functional role, since their replacement with Ala in the sequence of NC(1-13)-NH2 leads to inactivity; (d) the N-terminal tetrapeptide Phe-Gly-Gly-Phe is essential for activity: its full length and flexibility appear to be required for NC receptor activation and/or occupation; (e) Phe4 and not Phe1 appears to be the residue involved in receptor activation, since the replacement of Phe1 with Leu has no effect, while that of Phe4 leads to inactivity. Results summarized in this paper indicate that the structural requirements of NC for occupation and activation of its receptor are different from that of opioids, particularly delta agonists.

Characterization of [Nphe1]nociceptin(1-13)NH2, a new selective nociceptin receptor antagonist

Abstract: Nociceptin (orphanin FQ) is a novel neuropeptide capable of inducing a variety of biological actions via activation of a specific G-protein coupled receptor However, the lack of a selective nociceptin receptor antagonist has hampered our understanding of nociceptin actions and the role of this peptide in pathophysiological states As part of a broader programme of research, geared to the identification and characterization of nociceptin receptor ligands, we report that the novel peptide [Nphe1]nociceptin(1-13)NH2 acts as the first truly selective and competitive nociceptin receptor antagonist and is devoid of any residual agonist activity [Nphe1]nociceptin(1-13)NH2 binds selectively to recombinant nociceptin receptors expressed in Chinese hamster ovary (CHO) cells (pKi 84) and competitively antagonizes the inhibitory effects of nociceptin (i) on cyclic AMP accumulation in CHO cells (pA2 60) and (ii) on electrically evoked contractions in isolated tissues of the mouse, rat and guinea-pig with pA2 values ranging from 60 to 64 [Nphe1]nociceptin(1-13)NH2 is also active in vivo, where it prevents the pronociceptive and antimorphine actions of intracerebroventricularly applied nociceptin, measured in the mouse tail withdrawal assay Moreover, [Nphe1]nociceptin(1-13)NH2 produces per se a dose dependent, naloxone resistant antinociceptive action and, at relatively low doses, potentiates morphine-induced analgesia Collectively our data indicate that [Nphe1]nociceptin(1-13)NH2, acting as a nociceptin receptor antagonist, may be the prototype of a new class of analgesics British Journal of Pharmacology (2000) 129, 1183–1193; doi:101038/sjbjp0703169

The Epidemiology of Venous Thromboembolism

Abstract: Venous thromboembolism (VTE) is categorized by the U.S. Surgeon General as a major public health problem. VTE is relatively common and associated with reduced survival and substantial health-care costs, and recurs frequently. VTE is a complex (multifactorial) disease, involving interactions between acquired or inherited predispositions to thrombosis and VTE risk factors, including increasing patient age and obesity, hospitalization for surgery or acute illness, nursing-home confinement, active cancer, trauma or fracture, immobility or leg paresis, superficial vein thrombosis, and, in women, pregnancy and puerperium, oral contraception, and hormone therapy. Although independent VTE risk factors and predictors of VTE recurrence have been identified, and effective primary and secondary prophylaxis is available, the occurrence of VTE seems to be relatively constant, or even increasing.

The epidemiology of venous thromboembolism

Abstract: Venous thromboembolism (VTE) is categorized by the U.S. Surgeon General as a major public health problem. VTE is relatively common and associated with reduced survival and substantial health-care costs, and recurs frequently. VTE is a complex (multifactorial) disease, involving interactions between acquired or inherited predispositions to thrombosis and VTE risk factors, including increasing patient age and obesity, hospitalization for surgery or acute illness, nursing-home confinement, active cancer, trauma or fracture, immobility or leg paresis, superficial vein thrombosis, and, in women, pregnancy and puerperium, oral contraception, and hormone therapy. Although independent VTE risk factors and predictors of VTE recurrence have been identified, and effective primary and secondary prophylaxis is available, the occurrence of VTE seems to be relatively constant, or even increasing.