Molecular pharmacology of the opioid/nociceptin system

Opium has been used for thousands of years as an analgesic and is a substance of abuse yet until recently its modes of action have remained largely unresolved. Three classical receptors for opioids have been cloned; MOP (μ), KOP (κ) and DOP (δ). Furthermore, an orphan receptor NOP has recently been identified. Endogenous agonists exist for MOP (endomorphins), KOP (dynorphins), DOP (enkephalins) and NOP (nociceptin/orphanin FQ or N/OFQ). There is substantial overlap between these G_i/o protein coupled classical opioid (MOP/KOP/DOP) and NOP systems in that activation of both results in; (1) decreased cAMP formation, (2) stimulation of K⁺ efflux, (3) inhibition of voltage-gated Ca²⁺ channels and (4) inhibition of neuronal activity. Activation of MOP/KOP/DOP produces varying degrees of analgesia with MOP agonists representing the mainstay of clinically used opioids. In addition to these functional similarities, receptor, peptide and genomic homology of the NOP–N/OFQ and MOP/KOP/DOP-opioid systems suggest a common family, supported by comparable distribution patterns in the central nervous system. At a systems level, N/OFQ produces analgesia spinally with anti-opioid actions observed supraspinally. NOP-N/OFQ pharmacology is rapidly evolving and we feel that the next class of clinically useful analgesics may target this system.     

Cardiovascular pharmacology: new drugs and new indications

This review presents a brief overview of some of the many exciting developments that are taking place in the field of cardiovascular pharmacology. Research continues to progress at a rapid rate, and we can expect many drugs to enter the clinical arena within the next few years. It must be borne in mind, however, that the pharmaceutical industry and hospital budgetary restrictions sometimes limit drug development and occasionally interrupt clinical trials, even before their results have been obtained.     

Mineralocorticoid receptor antagonists: the evolution of utility and pharmacology

For more than 30 years after the discovery of aldosterone, scientists believed that its sole site of action was at epithelial tissues, most notably the kidney, where it mediated the transport of Na and K. It was soon recognized aldosterone contributed to several diseases by causing edema. Armed with this information, scientists set out more than 30 years ago to develop an antagonist of the mineralocorticoid receptor for the treatment of edematous states. From this effort, spironolactone (Aldactone was discovered. Spironolactone acts functionally as a competitive inhibitor of the mineralocorticoid (aldosterone) receptor, and although spironolactone is an effective mineralocorticoid receptor antagonist, it is not without limitations. These limitations include unwanted progestational and antiadrogenic side effects that limit its use in the chronic treatment of disease. In addition to its actions at the collecting tubule, aldosterone can participate in pathophysiology by actions at the heart, vasculature, and kidney, and it is likely that the most significant contributions to cardiovascular disease are due to actions at these sites rather than those related to Na and water retention. This is underscored by the recent clinical results from the RALES-004 Trial in which treatment with Aldactone demonstrated a significant benefit on mortality in patients with severe heart failure. The limited utility of spironolactone owing to the aforementioned steroid-related side effects has been especially frustrating, given the newly recognized role of aldosterone in cardiovascular disease. To obviate these limitations, eplerenone is currently being developed by Searle. Eplerenone is a competitive antagonist of the mineralocorticoid receptor that takes advantage of replacing the 17alpha-thoacetyl group of spironolactone with a carbomethoxy group, conferring excellent selectivity for the mineralocorticoid receptor over other steroid receptors. The pharmacological profile of eplerenone positions it to be an effective and selective mineralocorticoid receptor antagonist.     

Sphingosine 1-phosphate receptor modulators: a new class of immunosuppressants

In this review, we summarize how FTY720 came from the lab bench to the bedside by examining its structural similarities to natural occurring sphingosine analogues, the mechanism of action, and clinical applicability to not only transplantation but also autoimmune, oncological, and neurobiological fields. FTY720, a sphingosine 1-phosphate (S1P) analogue, promotes the survival of human and animal allografts by sequestering T lymphocytes within peripheral lymphoid tissue. The mechanism of sequestration is three-fold: (1) T lymphocytes are driven into peripheral lymph nodes in a chemokine dependent manner by FTY720; (2) FTY720 downregulates sphingosine 1-phosphate receptors (S1PRs) on the T lymphocyte surface, rendering it unable to migrate along a S1P gradient; and (3) FTY720 closes stromal gates on the abluminal side of the lymphatic endothelium. Future areas of investigation include developing S1P analogues that have specific agonist binding to S1PRs avoiding side effects seen in non-specific binding.     

The role of opioid receptor internalization and beta-arrestins in the development of opioid tolerance

Opioid tolerance, a phenomenon characterized by decreased analgesic effects obtained by the same dose of opioids after repeated use of the opioids, is a significant clinical problem. Traditional theory attributes receptor desensitization and internalization and post-receptor adaptation to the development of opioid tolerance. However, morphine, a commonly used opioid, induces tolerance but is not an effective drug to induce opioid receptor desensitization and internalization. Recent studies found that internalized opioid receptors can become competent receptors and recycle back to the cell surface membrane after dephosphorylation. Thus, receptor internalization may be a way to reduce opioid tolerance. Multiple studies have suggested a key role of beta-arrestins in opioid receptor desensitization and internalization and opioid tolerance. Although beta-arrestin 1 and beta-arrestin 2 are important for these effects induced by opioids with high intrinsic efficacy such as etorphine and fentanyl, morphine tolerance may be mediated mainly via beta-arrestin 2. Modification of opioid receptor internalization by affecting the interaction between opioid receptors and beta-arrestins may be a therapeutic target for reducing opioid tolerance.     

The role of the spinal opioid receptor like1 receptor, the NK-1 receptor, and cyclooxygenase-2 in maintaining postoperative pain in the rat.

Postoperative incident pain is not easily treated with opioids. Mechanical hyperalgesia induced by skin incision in rats is one of the animal models of postoperative incident pain. It is thought that mechanical hyperalgesia is maintained by the sensitization of spinal dorsal horn neurons. The NK-1 receptor, the opioid receptor like1 (ORL1) receptor, and cyclooxygenase (COX)-2 reportedly are involved in the development of spinal sensitization. In this study, we clarified the role of the NK-1 receptor, the ORL1 receptor, and COX-2 in the maintenance of mechanical hyperalgesia induced by skin incision. A 1-cm longitudinal incision was made through skin and fascia of the plantar aspect of the right foot in the rat. Four hours after the skin incision, significant mechanical hyperalgesia developed. An ORL1 receptor agonist (nociceptin), NK-1 receptor antagonists (CP-96,345 and FK888), and COX-2 inhibitors (NS398 and JTE522) were administered intrathecally 4 h after the skin incision. An ORL1 receptor agonist and NK-1 receptor antagonists, but not COX-2 inhibitors, significantly attenuated the level of mechanical hyperalgesia induced by the skin incision. These findings suggest that the spinal ORL1 receptor and the NK-1 receptor play an important role in maintaining the mechanical hyperalgesia induced by skin incision. IMPLICATIONS: Intrathecal injection of an NK-1 receptor antagonist and an ORL1 receptor agonist may be effective for the treatment of postoperative incident pain.     

Chemokine receptor CCR1: a new target for progressive kidney disease

Infiltrating leukocytes are thought to contribute to the progression of kidney disease. Locally produced chemokines guide circulating leukocytes into the kidney, which renders therapeutic blockade of respective chemokine receptors on the leukocyte surface as potential targets for the inhibition of renal leukocyte recruitment. By using mutant mice and specific antagonists, we found that chemokine receptor CCR1 has non-redundant functions for leukocyte adhesion to activated vascular endothelium and for transendothelial diapedesis. Most importantly, CCR1 blockade with a specific small molecule antagonist can improve injury in several types of progressive kidney disease models, even if treatment is initiated in advanced disease states. Identification of new targets may add to the therapeutic options in chronic kidney disease.     

Central analgesic mechanisms: a review of opioid receptor physiopharmacology and related antinociceptive systems.

Clinical applications of these principles, based on the increased understanding of central analgetic mechanisms, are already being undertaken. Not only does the use of intrathecal and epidural opioids have the potential to decrease pain and related morbidity after surgical procedures, but there is at least one study that demonstrates a significant reduction in both major morbidity and mortality in high-risk surgical patients in whom epidural anesthesia and analgesia were used. These principles are also useful for the management of patients undergoing cardiac surgery. Currently, high-dose narcotic anesthesia is the technique of choice for such patients because of the greater hemodynamic stability this anesthetic technique provides. However, breakthrough hypertension and tachycardia still occur, and prolonged postoperative ventilation is a necessary consequence due to the high doses of narcotics that are required. In one study of patients undergoing coronary artery surgery, preoperative administration of clonidine, 5 micrograms/kg, orally, was demonstrated to decrease fentanyl requirements by 45% (110 to 61 micrograms/kg) while producing a similar degree of hemodynamic stability as seen with high-dose fentanyl. Extubation times were not compared, but the significantly lower dosage of fentanyl in the clonidine-treated group would be expected to lead to an earlier extubation. Whether similar potentiation of narcotic effects would be seen with dexmedetomidine, which may also prevent narcotic-induced rigidity, has not been determined, but the clinical application of such synergistic and complementary agents is another consequence of the greater understanding of central analgesic mechanisms, and augurs well for the future.     

The pharmacology of recombinant hirudin, a new anticoagulant

A new anticoagulant, recombinant hirudin, was given to healthy volunteers (5 per test dose) in single intravenous doses of 0.01, 0.02, 0.04, 0.07 and 0.1 mg/kg to study its anticoagulant effects, how it was tolerated and its pharmacokinetics. Hirudin proved to be a potent anticoagulant with important effects on thrombin (increase in thrombin time and partial thromboplastin time). The maximum pharmacodynamic effect was achieved with the 0.07 mg/kg dose, and upwards. All doses of the compound were tolerated without side-effects. The mean elimination half-life is about 1 hour. Mean total clearance and volume of distribution are approximately 190 ml/min and 14 l, respectively. Hirudin obeys first-order pharmacokinetics.     

The pharmacokinetics of alfentanil (R39209): a new opioid analgesic

The pharmacokinetics of alfentanil (R39209), a new short-acting opioid analgesic, have been studied in eleven patients. Six patients were given 50 micrograms/kg alfentanil and five patients 125 micrograms/kg as an intravenous bolus injection. Plasma concentrations were measured at intervals up to 6 h (50 micrograms/kg) or 8-10 h (125 micrograms/kg), using a specific radioimmunoassay technique. Plasma concentrations declined triexponentially in both groups. The initial elimination of alfentanil from the plasma was very rapid with 90% of the administered dose leaving the plasma within 30 min. The average half-lives for the three phases were similar for both groups. The combined mean (+/- SEM) half-lives for the 11 patients for the rapid and slow distribution phases were short (t 1/2 pi = 1.2 +/- 0.26 min, t 1/2 alpha = 11.6 +/- 1.63 min). The elimination half-life, t 1/2 beta was 94 +/- 5.87 min which is considerably shorter than that of other opioids. The mean (+/- SEM) total body clearance was 6.4 +/- 1.39 ml . kg-1 . min-1 and the volume of distribution (Vd) was 0.86 +/- 0.194 l/kg. The latter is considerably less than reported values for the chemically related drug, fentanyl, and suggests that alfentanil may have a lower tissue binding affinity than fentanyl. The rapid elimination and short duration of clinical action suggests the feasibility of repeated administration of alfentanil and its use by continuous intravenous infusion.     

Studies of the pharmacology of a new antidepressant, S1694.

A new antidepressive drug, S1694, produces increased locomotor activity (LA) in mice, but less so than d-amphetamine. This effect is decreased by pimozide, phenoxybenzamine, as well as by pretreatment of the animals with reserpine or alpha-methyl-p-tyrosine methyl ester (H44/68). S1694 inhibits active dopamine (DA) uptake into rat striatal synaptosomes, but not noradrenaline (NA) uptake into rat hypothalamic synaptosomes, or serotonin (5-HT) uptake into rat midbrain synaptosomes, in the concentrations used. The inhibition of DA uptake appears tp be competitive and the inhibition constant estimated is 1,3 X 10(-6) M. In addition, S1694 releases DA in the same concentrations, and NA as well as 5HT at higher concentrations. It is concluded that S1694 activates LA primarily by inhibitionof DA re-uptake and DA release. The central DA system activation may be important in the antidepressive effect.     

Multiple opioid receptor systems in brain and spinal cord: Part I

The biological activity of opioid agents reflects their interaction with specific membrane sites. The fact that the drug interaction resulting in physiological responses shows distinguishing characteristics with regard to rank order of agonist potency, affinity of the antagonist for the site acted upon by the agent to produce the effect, tolerance and cross-tolerance, may be interpreted as indicating that different opioids produce their effects by an action on distinctive receptors. Examination of the literature provides support for the hypothesis proposed by different investigators that the physiological effects of the several opioid ligands may be parsimoniously explained in terms of several possibly overlapping receptor classes including mu, delta, kappa, sigma and epsilon. Binding studies examining the affinity of the ligand for a tissue site have in general provided confirming support for these receptor profiles. It is stressed that the majority of the documentation for receptor classes derives from in vitro work. However, a growing number of quantitative studies of the receptors in brain which regulate central nervous system processing are also showing evidence of definable differences in drug action which are comparable to those reported for in vitro bioassays and binding studies. Examination of the pharmacology of the analgesic effects of opioids indicates that the differences in the activity of opioid drugs (such as between mu and kappa agonists) probably reflect the role of different pain processing systems. Though not reviewed, it is likely that a similar complexity underlies the interaction of opioids with neural substrates mediating other functions. Thus different opioid receptors may modulate the same physiological phenomenon because they are on different systems which have a similar output (e.g. spinal reflex inhibition) or they may co-exist on the same neurone. In short, it appears likely that there are discriminable populations of opioid receptors and that no single receptor can be said to modulate a given physiological effect.     

RGS proteins: new players in the field of opioid signaling and tolerance mechanisms

In this article we review recent advances in our understanding of the crucial role of the Regulator of G protein Signaling (RGS) proteins in opioid signaling mechanisms and opioid tolerance development. Opioids exert their physiologic effects via complex G protein-coupled receptor-signaling mechanisms, and RGS proteins are now known to tightly regulate the G protein signaling cycle. RGS proteins contain GTPase-accelerating protein activity within their characteristic RGS domain and various other receptor signaling-related properties of their other functional domains. There have been more than 20 RGS proteins reported in the literature, and multiple RGS proteins have been shown to negatively regulate G protein-mediated opioid signaling, facilitate opioid receptor desensitization and internalization, and affect the rate at which opioid tolerance develops. Using RGS proteins as targets for future drug therapy aimed at modulating opioid effectiveness in both acute and chronic pain settings may be an important advance in the treatment of pain.     

New drugs and new understandings of paediatric pharmacology

Canadian Journal of Anesthesia/Journal canadien d'anesthésie -