Comparison of the antinociceptive profiles of morphine and oxycodone in two models of inflammatory and osteoarthritic pain in rat.

Oxycodone and morphine are two opioid drugs commonly used for the treatment of moderate to severe pain. However, their use in the management of noncancer pain remains a controversial issue and, in this respect, the evidence on their effectiveness and safety, particularly in osteoarthritis, is being questioned. In order to analyse their analgesic profile, two different pain models in rats were used: the formalin-induced inflammatory pain and the monosodium iodoacetate (MIA)-induced knee osteoarthritic pain. Drugs were administered systemically (i.p.) and their antinociceptive effect and potency were assessed. In the formalin test, both morphine and oxycodone produced a dose-dependent antinociceptive effect, but oxycodone outdid morphine in terms of effectiveness and potency (nearly two times) in the early (acute nociceptive) as in the late phase (inflammatory). In the osteoarthritis model, both drugs reduced movement-evoked pain (knee-bend test), mechanical allodynia (von Frey test) and heat hyperalgesia (Plantar test). Pretreatment with naloxone and naloxone methiodide reduced morphine and oxycodone effects. Peripheral mu-opioid receptors play a crucial role in the antinociceptive effect of both drugs on movement-evoked pain and heat hyperalgesia, but not on tactile allodynia. The main finding of our study is that oxycodone has a better antinociceptive profile in the inflammatory and osteoarthritic pain, being more effective than morphine at 14 days post-MIA injection (phase with neuropathic pain); it overcame the morphine effect by improving the movement-induced pain, tactile allodynia and heat hyperalgesia. Therefore, oxycodone could be an interesting option to treat patients suffering from knee osteoarthritis when opioids are required.

To what extent are specific psychotherapies for borderline personality disorders efficacious? A systematic review of published randomised controlled trials.

INTRODUCTION: Over the past 20 years, several studies have established the efficacy of different forms of psychotherapy for borderline personality disorders (BPD). However, existing research has used a wide range of outcomes measures which makes it difficult to quantify data and to compare interventions. This review has been designed to analyse the evidence from randomized controlled trials (RCT) through a qualitative approach. METHODS: A systematic review of published RCT on specific psychotherapies for BPD has been undertaken to find relevant literature from online PsycINFO, ISI Web of Knowledge and Medline databases. An analysis of variability in primary outcomes, dropout patients and those who do not enter treatment has been conducted to assess if a wide range of variation could show any potential bias. RESULTS: There is a substantial variation between the studies in primary outcomes, such as suicide attempts (7.4- 33.9%), and specially in dropout patients (6.7-47.4%) and those who do not enter treatment (17.6-63.6%). Globally, specific psychotherapy for BPD, at least in a 40% of patients who demand treatment, would not be efficacious. CONCLUSIONS: The overall efficacy of specific therapies for BPD is promising. However, the variability of results raise questions about potential bias. Future studies should investigate new therapeutic approaches to allow the management of more severe and refractory patients.

Cannabinoid/agonist WIN 55,212-2 reduces cardiac ischaemia­reperfusion injury in Zucker diabetic fatty rats: role of CB2 receptors and iNOS/eNOS.

BACKGROUND: Diabetes increases cardiac damage after myocardial ischaemia. Cannabinoids can protect against myocardial ischaemia/reperfusion injury. The aim of this study was to examine the cardioprotective effect of the cannabinoid agonist WIN 55,212-2 (WIN) against ischaemia/reperfusion injury in an experimental model of type 2 diabetes. We performed these experiments in the Zucker diabetic fatty rat, and focused on the role of cannabinoid receptors in modulation of cardiac inducible nitric oxide synthase (iNOS)/endothelial-type nitric oxide synthase (eNOS) expression. METHODS: Male 20-week-old Zucker diabetic fatty rats were treated with vehicle, WIN, the selective CB1 or CB2 receptor antagonists AM251 and AM630, respectively, AM251 + WIN or AM630 + WIN. Hearts were isolated from these rats, and the cardiac functional response to ischaemia/reperfusion injury was evaluated. In addition, cardiac iNOS and eNOS expression were determined by western blot. RESULTS: WIN significantly improved cardiac recovery after ischaemia/ reperfusion in the hearts from Zucker diabetic fatty rats by restoring coronary perfusion pressure and heart rate to preischaemic levels. Additionally, WIN decreased cardiac iNOS expression and increased eNOS expression after ischaemia/reperfusion in diabetic hearts. WIN-induced cardiac functional recovery was completely blocked by the CB2 antagonist AM630. However, changes in NOS isoenzyme expression were not affected by the CB antagonists. CONCLUSIONS: This study shows a cardioprotective effect of a cannabinoid agonist on ischaemia/reperfusion injury in an experimental model of a metabolic disorder. The activation mainly of CB2 receptors and the restoration of iNOS/eNOS cardiac equilibrium are mechanisms involved in this protective effect. These initial studies have provided the basis for future research in this field.

Contributions of peripheral and central opioid receptors to antinociception in rat muscle pain models.

Administration of hypertonic saline (HS) is an accepted model to study muscular pain. HS-induced nociceptive responses were tested in masseter, already described, and in two new pain models of spinally innervated muscles (gastrocnemius and triceps) developed in rats at our laboratory. HS administration in the masseter induced vigorous hindpaw shaking and in the gastrocnemius or triceps, paw withdrawal or flexing. Participation of the central and peripheral opioid receptors in HS-induced pain is compared in these muscles: masseter, innervated by trigeminal nerve, and gastrocnemius and triceps by spinal nerves. Morphine and loperamide were used to reveal peripheral and central components of opioid analgesia. Both agonists reduced HS-induced nociceptive behaviours in the masseter and were antagonised by the opioid antagonist naloxone and by naloxone methiodide, an opioid receptor antagonist that poorly penetrates the blood-brain barrier. Unexpectedly, in the gastrocnemius and triceps, morphine, but not loperamide, decreased the nociceptive behaviour and this effect was only reversed by naloxone. So, peripheral opioid receptors seem to participate in HS-induced masseter pain, whereas only central opioid receptors reduced the nociception in gastrocnemius and triceps. Our results suggest that the use of peripheral opioids can be more advantageous than central opioids for treatment of orofacial muscular pain.

Vasorelaxation caused by cannabinoids: mechanisms in different vascular beds.

Cannabinoids (natural, endogenous and synthetic compounds) produce vasorelaxation in resistance and conduit arteries. Several putative mechanisms have been proposed to explain this effect of cannabinoids. The aim of the present review is to discuss the different mechanisms involved in the vasorelaxant effect of endogenous and synthetic cannabinoids in resistance and conduit arteries. Research on the vascular effects of cannabinoids suggests that the magnitude of the vasorelaxation and the mechanisms involved are not identical in all vascular beds with one or two mechanisms predominating. Either extracellular or intracellular mechanisms are involved. With regard to the former, the stimulation of cannabinoid CB1, CB2 or nonCB1/nonCB2 cannabinoid receptors and the stimulation of vanilloid receptors, transient potential vanilloid receptors, on perivascular nerve endings with the subsequent release of the vasodilator neurotransmitter calcitonin gene-related peptide have been described. With regard to the latter, the main mechanisms implicated include nitric oxide release, metabolism to vasoactive arachidonic metabolites or prostanoid analogues, or endothelium derived hyperpolarising factor release. The knowledge of these mechanisms is crucial to identify new therapeutic targets and to understand the consequences in different vascular beds.

Altered feeding behaviour induced by long-term cisplatin in rats.

In animals without the emetic reflex, several emetogenic stimuli induce pica, an altered feeding behaviour consisting of the ingestion of non-nutritive substances. The development of pica in response to an emetogenic stimulus has been proposed to be useful as an indirect marker of nausea in the rat. In fact, like nausea and emesis in humans, it is accompanied by serotonin release from the enterochromaffin cells, increased c-fos labelling in the area postrema and the nucleus tractus solitarius, and a delay in gastric emptying. Furthermore, pica, measured as kaolin intake, is reduced by anti-emetic drugs. Pica has been demonstrated after single doses of cisplatin, the most emetogenic chemotherapeutic drug. However, cisplatin, as other antineoplastic drugs, is generally given in cycles, where conventional anti-emetics tend to lose efficiency. The aim of this work was to evaluate the pica induced by long-term treatment with cisplatin. Saline or cisplatin was administered once a week for 5 consecutive weeks, and temperature, body weight, food ingestion and kaolin intake were measured on a daily basis. The influence of isolation (pica is necessarily studied in isolated animals) and exposure to kaolin (basal kaolin intake could modify pica itself and other parameters) on temperature, body weight and daily food ingestion was negligible in saline-treated rats. Cisplatin administered at 3 mg/kg/week was too toxic: it produced hypothermia, weight drop and anorexia in both grouped and isolated rats, and 50% mortality in isolated animals. Toxicity associated with cisplatin administered at 1 mg/kg/week was acceptable, with a slower rate of weight gain being the major effect. In these rats, each cisplatin injection produced both acute anorexia and rebound hyperphagic responses. In addition, each administration induced both acute pica and an increase in basal kaolin intake, resembling the development of nausea in humans. This model could be useful for studying both the mechanisms leading to nausea associated with a long-term antineoplastic treatment and the efficiency of new anti-emetic drugs.

Synthesis and analgesic activity of a series of new azaalkane bis-guanidinium and bis(2-aminoimidazolinium) compounds.

In the present paper, we wish to report the synthesis and antinociceptive activity of a series of new azaalkane bis(2-aminoimidazolinium) compounds from which, N,N'-di(4,5-dihydro-1H-imidazol-2-yl)-3-aza-1,6-hexanediamine 2a has shown the best analgesic properties in vivo in two different assays (i.e., acetic acid-induced writhing test and hot-plate test in mice), as well as oral bioavailability.

Synthesis and opioid activity of new fentanyl analogs.

Three new fentanyl analogs (compounds 3-4-5) have been synthesized and evaluated for antinociceptive properties using the writhing test. The analgesic property of the active compound, N-[1-phenylpyrazol-3-yl]-N-[1-(2-phenethyl)-4-piperidyl)] propenamide (compound 4), was tested using the hot plate test in mice. Its opioid agonistic activity was characterized using three isolated tissues: guinea pig ileum, mouse vas deferens, and rabbit vas deferens. Compound 4 was as effective as fentanyl or morphine and it showed less antinociceptive potency than fentanyl but it was more potent than morphine. The duration of the antinociception was similar to that of fentanyl. This compound inhibited the electrically evoked contractions of myenteric plexus-longitudinal muscle strips of guinea pig ileum and of mouse vas deferens but not those of rabbit vas deferens. These effects could be reversed by micro selective antagonists (naloxone and/or CTOP) but not by the delta selective antagonist naltrindole, thus indicating that the compound acted as a micro opioid agonist. Finally, the binding data confirmed that compound 4 had high affinity and selectivity for the micro-receptor.

Guanidinium and aminoimidazolinium derivatives of N-(4-piperidyl)propanamides as potential ligands for mu opioid and I2-imidazoline receptors: synthesis and pharmacological screening.

Derivatives of N-(1-phenethyl-4-piperidyl)propanamides incorporating guanidinium and 2-aminoimidazolinium groups have been prepared by a synthetic approach involving first introduction of a spacer between the piperidine and the functional group by reductive amination of piperidinone. The formation of each of these functional groups was carried out using N-N'-di(tert-butoxycarbonyl)thiourea and 2-methylthioimidazolinium iodide, respectively. These structures have been designed to incorporate two pharmacologic goals into one entity. Radioligand binding assays have been used to study their affinity for opioid (mu, delta and kappa) and I2-imidazoline receptors. Two of them, 10 and 16, showed high affinity for mu opioid receptors and functionally they had moderate analgesic properties in the hot plate and writhing tests. The in vitro studies on guinea pig ileum (GPI) indicated that both compounds are mu opioid agonists. In what concerns I2-imidazoline receptor activity, these derivatives showed low affinity around 6 to 7 times less than idazoxan.