Synergistic interaction between the agonism of cebranopadol at nociceptin/orphanin FQ and classical opioid receptors in the rat spinal nerve ligation model.

Cebranopadol (trans-6'-fluoro-4',9'-dihydro--dimethyl-4-phenyl-spiro[cyclohexane-1,1'(3'H)-pyrano[3,4-b]indol]-4-amine) is a novel analgesic nociceptin/orphanin FQ opioid peptide (NOP) and classical opioid receptor (MOP, DOP, and KOP) agonist with highly efficacious and potent activity in a broad range of rodent models of nociceptive, inflammatory, and neuropathic pain as well as limited opioid-type side effects such as respiratory depression. This study was designed to explore contribution and interaction of NOP and classical opioid receptor agonist components to cebranopadol analgesia in the rat spinal nerve ligation (SNL) model. Assessing antihypersensitive activity in SNL rats intraperitoneal (IP) administration of cebranopadol resulted in ED values of 3.

Cebranopadol: a novel potent analgesic nociceptin/orphanin FQ peptide and opioid receptor agonist.

Cebranopadol (trans-6'-fluoro-4',9'-dihydro-N,N-dimethyl-4-phenyl-spiro[cyclohexane-1,1'(3'H)-pyrano[3,4-b]indol]-4-amine) is a novel analgesic nociceptin/orphanin FQ peptide (NOP) and opioid receptor agonist [Ki (nM)/EC50 (nM)/relative efficacy (%): human NOP receptor 0.9/13.0/89; human mu-opioid peptide (MOP) receptor 0.

Spinal-supraspinal and intrinsic μ-opioid receptor agonist-norepinephrine reuptake inhibitor (MOR-NRI) synergy of tapentadol in diabetic heat hyperalgesia in mice.

Tapentadol is a μ-opioid receptor (MOR) agonist and norepinephrine reuptake inhibitor (NRI) with established efficacy in neuropathic pain in patients and intrinsic synergistic interaction of both mechanisms as demonstrated in rodents. In diabetic mice, we analyzed the central antihyperalgesic activity, the occurrence of site-site interaction, as well as the spinal contribution of opioid and noradrenergic mechanisms in a hotplate test. Tapentadol (0.

Pharmacological and behavioral profile of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-chinolincarboxamide (EVP-5141), a novel α7 nicotinic acetylcholine receptor agonist/serotonin 5-HT3 receptor antagonist.

Rationale And Objective: Agonists of α7 nicotinic acetylcholine receptors (nAChRs) may have therapeutic potential for the treatment of cognitive deficits. This study describes the in vitro pharmacology of the novel α7 nAChR agonist/serotonin 5-HT3 receptor (5-HT3R) antagonist N-[(3R)-1-azabicyclo[2.2.

Tapentadol increases levels of noradrenaline in the rat spinal cord as measured by in vivo microdialysis.

Spinal noradrenaline is thought to play an important role in descending pain inhibitory pathways and the modulation of nociceptive information at the spinal level. Tapentadol is a μ-opioid receptor (MOR) agonist and noradrenaline reuptake inhibitor (NRI). We showed previously that tapentadol, in contrast to morphine, elevates levels of noradrenaline, but not serotonin, in the ventral hippocampus of rats.

Antinociceptive and antihyperalgesic effects of tapentadol in animal models of inflammatory pain.

The novel analgesic tapentadol HCl [(-)-(1R,2R)-3-(3-dimethylamino)-1-ethyl-2-methyl-propyl)-phenol hydrochloride] combines μ-opioid receptor (MOR) agonism and noradrenaline reuptake inhibition (NRI) in a single molecule and shows a broad efficacy profile in various preclinical pain models. This study analyzed the analgesic activity of tapentadol in experimental inflammatory pain. Analgesia was evaluated in the formalin test (pain behavior, rat and mouse), carrageenan-induced mechanical hyperalgesia (paw-pressure test, rat), complete Freund's adjuvant (CFA)-induced paw inflammation (tactile hyperalgesia, rat), and CFA knee-joint arthritis (weight bearing, rat).

Synergistic antihypersensitive effects of pregabalin and tapentadol in a rat model of neuropathic pain.

Neuropathic pain is a clinical condition which remains poorly treated and combinations of pregabalin, an antagonist of the α2δ-subunit of Ca(2+) channels, with tapentadol, a μ-opioid receptor agonist/noradrenaline reuptake inhibitor, or with classical opioids such as oxycodone and morphine might offer increased therapeutic potential. In the rat spinal nerve ligation model, a dose dependent increase in ipsilateral paw withdrawal thresholds was obtained using an electronic von Frey filament after IV administration of pregabalin (1-10mg/kg), tapentadol (0.316-10mg/kg), morphine (1-4.

Critical evaluation of the use of extinction paradigms for the assessment of opioid-induced conditioned place preference in rats.

The rewarding effects of drugs of abuse are often studied by means of the conditioned place preference (CPP) paradigm. CPP is one of the most widely used models in behavioral pharmacology, yet its theoretical underpinnings are not well understood, and there are very few studies on the methodological and theoretical aspects of this model. An important drawback of the classical CPP paradigm is that it often does not show dose-dependent results.

The antinociceptive and antihyperalgesic effect of tapentadol is partially retained in OPRM1 (μ-opioid receptor) knockout mice.

Activation of the μ-opioid receptor (MOR) and noradrenaline reuptake inhibition (NRI) are well recognized as analgesic principles in acute and chronic pain indications. The novel analgesic tapentadol combines MOR agonism and NRI in a single molecule. The present study used OPRM1 (MOR) knockout (KO) mice to determine the relative contribution of MOR activation to tapentadol-induced analgesia in models of acute (nociceptive) and chronic (neuropathic) pain.

Pharmacological blockade or genetic knockout of the NOP receptor potentiates the rewarding effect of morphine in rats.

The Nociceptin/OrphaninFQ (NOP) system is believed to be involved in drug abuse and addiction. We have recently demonstrated that activation of the NOP receptor, by systemic administration of the NOP receptor agonist Ro65-6570, attenuated the rewarding effect of various opioids in conditioned place preference (CPP) in rats and this attenuating effect was reversed by the NOP receptor antagonist J-113397. The present study demonstrates that co-administration of J-113397 (4.

Dissociation of rewarding, anti-aversive and anti-nociceptive effects of different classes of anti-nociceptives in the rat.

It was previously shown that morphine more potently reduces the affective as compared to the sensory component of nociception, and this effect is independent of morphine's rewarding properties. Here we investigated whether this finding can be generalized to other classes of anti-nociceptive drugs. The effect of oxycodone (0-10 mg/kg, i.

Effects of the NOP receptor agonist Ro65-6570 on the acquisition of opiate- and psychostimulant-induced conditioned place preference in rats.

Activation of the Nociceptin/Orphanin FQ (NOP) receptor may have anti-abuse effects. The present study examined the consequence of NOP receptor activation on the rewarding effect of opiates and psychostimulants in the conditioned place preference task in rats. First, the motivational effect of the NOP receptor agonists Ro64-6198 (0.

The mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) potentiates conditioned place preference induced by various addictive and non-addictive drugs in rats.

We have recently reported that the metabotropic glutamate receptor 5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) potentiates acquisition of conditioned place preference (CPP) induced by heroin and ketamine. The present study investigated to what extent this effect of MPEP can be generalized to other classes of drugs, such as the stimulants nicotine and cocaine, and to drugs that produce CPP in the rat despite a lack of abuse potential in humans, such as buspirone and clonidine. Adult male Sprague Dawley rats were subjected to a standard unbiased CPP protocol (six conditioning sessions lasting 20 minutes for nicotine and 40 minutes for the other compounds).

Differential contribution of opioid and noradrenergic mechanisms of tapentadol in rat models of nociceptive and neuropathic pain.

The novel analgesic tapentadol combines mu-opioid receptor agonism and noradrenaline reuptake inhibition in a single molecule and shows potent analgesia in various rodent models of pain. We analyzed the contribution of opioid and monoaminergic mechanisms to the activity of tapentadol in rat models of nociceptive and neuropathic pain. Antinociceptive efficacy was inferred from tail withdrawal latencies of experimentally naive rats using a tail flick test.

Tapentadol, but not morphine, selectively inhibits disease-related thermal hyperalgesia in a mouse model of diabetic neuropathic pain.

Neuropathic pain in diabetic patients is a common distressing symptom and remains a challenge for analgesic treatment. Selective inhibition of pathological pain sensation without modification of normal sensory function is a primary aim of analgesic treatment in chronic neuropathic pain. Tapentadol is a novel analgesic with two modes of action, mu-opioid receptor (MOR) agonism and noradrenaline (NA) reuptake inhibition.

Tapentadol hydrochloride: a next-generation, centrally acting analgesic with two mechanisms of action in a single molecule.

Tapentadol exerts its analgesic effects through micro opioid receptor agonism and noradrenaline reuptake inhibition in the central nervous system. Preclinical studies demonstrated that tapentadol is effective in a broad range of pain models, including nociceptive, inflammatory, visceral, mono- and polyneuropathic models. Moreover, clinical studies showed that tapentadol effectively relieves moderate to severe pain in various pain care settings.

The mGlu5 receptor antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP) supports intravenous self-administration and induces conditioned place preference in the rat.

We recently reported that the mGlu5 receptor antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP) reduces intravenous self-administration of ketamine and, to a lesser extent, heroin in rats. We also found that MPEP potentiates conditioned place preference induced by these drugs, suggesting that the reduction of self-administration results from an MPEP-induced potentiation of the rewarding effect of the self-administered drug. The aim of the present study was to examine whether MPEP has intrinsic positive reinforcing and rewarding effects.

2-Methyl-6-(phenylethynyl)-pyridine (MPEP) potentiates ketamine and heroin reward as assessed by acquisition, extinction, and reinstatement of conditioned place preference in the rat.

The mGlu(5) receptor antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP) has been shown to reduce intravenous self-administration of ketamine and, to a limited extent, heroin in rats. We investigated whether MPEP affects the rewarding effect of ketamine and heroin as assessed in a conditioned place preference (CPP) paradigm. Sprague Dawley rats were subjected to a standard unbiased CPP protocol.

Investigation of TRPV1 loss-of-function phenotypes in transgenic shRNA expressing and knockout mice.

The function of the transient receptor potential vanilloid 1 (TRPV1) cation channel was analyzed with RNA interference technologies and compared to TRPV1 knockout mice. Expression of shRNAs targeting TRPV1 in transgenic (tg) mice was proven by RNase protection assays, and TRPV1 downregulation was confirmed by reduced expression of TRPV1 mRNA and lack of receptor agonist binding in spinal cord membranes. Unexpectedly, TRPV3 mRNA expression was upregulated in shRNAtg but downregulated in knockout mice.

Effect of 2-methyl-6-(phenylethynyl) pyridine on intravenous self-administration of ketamine and heroin in the rat.

The mGluR5 antagonist 2-methyl-6-(phenylethynyl) pyridine (MPEP) may be beneficial for drug abuse treatment, as it has been found to reduce self-administration of ethanol, nicotine and cocaine in preclinical models. This study investigated whether this finding can be extended to dissociative anaesthetics and opioids. Long Evans rats were trained to intravenously self-administer ketamine (0.

Differential effects of morphine on the affective and the sensory component of carrageenan-induced nociception in the rat.

Pain is generally considered to have a sensory and an affective component. Clinical research has suggested that morphine more potently attenuates the affective component as compared to the sensory component. Because preclinical nociception models typically focus on the sensory component of nociception, and do not assess the affective component, it is unclear whether this potency difference of morphine can also be found in preclinical models.

(-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol hydrochloride (tapentadol HCl): a novel mu-opioid receptor agonist/norepinephrine reuptake inhibitor with broad-spectrum analgesic properties.

(-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol hydrochloride (tapentadol HCl) is a novel micro-opioid receptor (MOR) agonist (Ki = 0.1 microM; relative efficacy compared with morphine 88% in a [35S]guanosine 5'-3-O-(thio)triphosphate binding assay) and NE reuptake inhibitor (Ki = 0.5 microM for synaptosomal reuptake inhibition).

The novel alpha7 nicotinic acetylcholine receptor agonist N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-[2-(methoxy)phenyl]-1-benzofuran-2-carboxamide improves working and recognition memory in rodents.

The relative contribution of alpha4beta2, alpha7 and other nicotinic acetylcholine receptor (nAChR) subtypes to the memory enhancing versus the addictive effects of nicotine is the subject of ongoing debate. In the present study, we characterized the pharmacological and behavioral properties of the alpha7 nAChR agonist N-[(3R)-1-azabicyclo[2.2.

Effects of venlafaxine and desipramine on heroin-induced conditioned place preference in the rat.

Venlafaxine, an antidepressant with serotonin and noradrenaline reuptake inhibiting properties, has been reported to reduce acquisition (but not maintenance) of heroin intravenous self-administration (IVSA) in rats. The present study investigated whether this phase-dependent effect is due to an antidepressant-induced attenuation of the rewarding effect of heroin, as assessed in the conditioned place preference (CPP) paradigm. In order to study the effects of venlafaxine and the tricyclic antidepressant desipramine on acquisition and expression of heroin CPP, both compounds were administered prior to the conditioning sessions (together with heroin), or prior to the expression test after conditioning, respectively.

The serotonin/noradrenaline reuptake inhibitor venlafaxine attenuates acquisition, but not maintenance, of intravenous self-administration of heroin in rats.

Opioids and antidepressants are frequently used for the treatment of various pain conditions. A combination of both drug classes may be more effective than either treatment alone, and combined treatment with an antidepressant may result in an opiate-sparing effect. Although it has been shown that antidepressants can attenuate self-administration of psychomotor stimulant and depressant drugs, it is not known whether they also attenuate self-administration of opiates.