J. De Vry

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 persistence of the conditioned response, i.e. the time required until the CPP effect is extinct, may be related to the strength of conditioning, which in turn may be related to the rewarding efficacy of a drug. Resistance to extinction may therefore be a useful additional measure to quantify the rewarding effect of drugs. In the present study we examined the persistence of drug-environment associations after conditioning with morphine (1, 3 and 10 mg/kg i.p.), oxycodone (0.3, 1 and 3 mg/kg i.p.) and heroin (0.05, 0.25 and 0.5 mg/kg i.p.) by repeated retesting in the CPP apparatus (15-min sessions, 5 days/week) until the rats reached extinction (i.e. less than 55% preference over 3 consecutive sessions). Following an unbiased CPP protocol, morphine, oxycodone and heroin induced CPP with minimal effective doses of 3, 1 and 0.25 mg/kg, respectively, and with similar effect sizes for each CPP-inducing dose. The number of sessions required for extinction was positively correlated with the dose of the drug (experiment 1: 18 and 45 sessions for 3 and 10 mg/kg morphine, and 19 and 27 sessions for 1 and 3 mg/kg oxycodone; experiment 2: 12 and 24 sessions for 3 and 10 mg/kg morphine, and 10 and 14 sessions for 0.25 and 0.5 mg/kg heroin). These findings suggest that the use of an extinction paradigm can extend the quantitative assessment of the rewarding effect of drugs – however, within certain limits only. The present paradigm appears to be less suited for comparing the rewarding efficacy of different drugs due to great test-retest variability. Finally, the additional potential gain of information using this paradigm has to be weighed against the considerably large amount of additional time and effort.

Tapentadol: mit zwei Mechanismen in einem Molekül wirksam gegen nozizeptive und neuropathische Schmerzen

Tapentadol (3-[(1R, 2R)-3-(dimethylamino)-1-ethyl-2-methylpropyl] phenol) is a centrally acting analgesic of a new substance class for the treatment of severe nociceptive and neuropathic pain. Tapentadol combines μ-opioid receptor (MOR) agonism and noradrenaline reuptake inhibition (NRI) in one molecule. Because of the combined mechanisms of action tapentadol offers a broad therapeutic spectrum for nociceptive as well as neuropathic pain. In different animal models its high efficacy was shown in acute nociceptive, acute and chronic inflammatory as well as in chronic neuropathic pain. Using several preclinical approaches it was shown that the noradrenergic component of tapentadol interacts with the opioid component and that both synergistically contribute to the analgesic effect of the substance. In comparison to known drugs with only one of the two modes of action, tapentadol, despite its high potency, has an improved tolerability profile in the relevant animal models, particularly with regard to gastrointestinal and central side effects. Tapentadol acts directly without metabolic activation and without formation of analgesically relevant metabolites. In different interaction studies a low potential for interactions was shown, thus clinically relevant drug-drug interactions are unlikely. Overall, tapentadol provides a safe pharmacodynamic-pharmacokinetic profile.ZusammenfassungTapentadol (3-[(1R, 2R)-3-(Dimethylamino)-1-Äthyl-2-Methylpropyl]-Phenol) ist ein zentral wirksames Analgetikum einer neuen Substanzklasse zur Behandlung starker nozizeptiver und neuropathischer Schmerzen. Tapentadol kombiniert µ-Opioid-Rezeptor (MOR)-Agonismus und Noradrenalin–Wiederaufnahmehemmung (NRI) in einem Molekül. Aufgrund des kombinierten Wirkmechanismus bietet Tapentadol ein breites Wirkspektrum sowohl im nozizeptiven als auch im neuropathischen Schmerz: In verschiedenen Schmerzmodellen am Tier konnte eine starke Wirksamkeit bei akut-nozizeptiven, akut- und chronisch-entzündlichen sowie bei chronisch-neuropathischen Schmerzen gezeigt werden.Mittels verschiedener präklinischer Ansätze konnte belegt werden, dass die noradrenerge Wirkkomponente in Tapentadol mit der opioidergen Komponente interagiert und beide synergistisch zur analgetischen Wirkung der Substanz beitragen. Im Vergleich zu bekannten Substanzen mit nur einem der beiden Wirkmechanismen besitzt Tapentadol in den entsprechenden Tiermodellen, trotz seiner hohen Potenz, ein verbessertes Verträglichkeitsprofil, insbesondere in Bezug auf gastrointestinale und zentralnervöse Nebenwirkungen.Tapentadol wirkt direkt, ohne metabolische Aktivierung und ohne Bildung analgetisch relevanter Metabolite. In verschiedenen Interaktionsstudien konnte ein geringes Interaktionspotenzial nachgewiesen werden, klinisch relevante Wechselwirkungen mit anderen Substanzen sind somit unwahrscheinlich. Insgesamt bietet Tapentadol also ein sicheres pharmakodynamisch-pharmakokinetisches Profil.AbstractTapentadol (3–[(1R, 2R)-3–(dimethylamino)-1-ethyl-2-methylpropyl] phenol) is a centrally acting analgesic of a new substance class for the treatment of severe nociceptive and neuropathic pain. Tapentadol combines μ-opioid receptor (MOR) agonism and noradrenaline reuptake inhibition (NRI) in one molecule. Because of the combined mechanisms of action tapentadol offers a broad therapeutic spectrum for nociceptive as well as neuropathic pain. In different animal models its high efficacy was shown in acute nociceptive, acute and chronic inflammatory as well as in chronic neuropathic pain.Using several preclinical approaches it was shown that the noradrenergic component of tapentadol interacts with the opioid component and that both synergistically contribute to the analgesic effect of the substance. In comparison to known drugs with only one of the two modes of action, tapentadol, despite its high potency, has an improved tolerability profile in the relevant animal models, particularly with regard to gastrointestinal and central side effects.Tapentadol acts directly without metabolic activation and without formation of analgesically relevant metabolites. In different interaction studies a low potential for interactions was shown, thus clinically relevant drug-drug interactions are unlikely. Overall, tapentadol provides a safe pharmacodynamic-pharmacokinetic profile.

317 ANTI‐NOCICEPTIVE ACTIVITY OF TAPENTADOL IN A RAT MODEL OF ACUTE PAIN DEPENDS ON OPIOID AND NORADRENERGIC, BUT NOT SEROTONERGIC, MECHANISMS

Descending facilitation from brainstem nuclei including the rostral ventromedial medulla (RVM) plays an important role in visceral pain, and compounds targeting the a2d subunit of voltage-gated calcium channels have demonstrated clinical efficacy in patients with visceral hyperalgesia. An in vivo model of visceral pain was established involving colorectal distension (CRD) in SpragueDawley rats. Evoked visceromotor responses (VMR) were quantified with reliable electromyographic recordings of activity in the external oblique muscle following colonic distension. Changes in VMR evoked by CRD in a range of 10–80mmHg were recorded before and after systemic pregabalin (30mg/kg s.c.) in naïve rats and rats pretreated with 0.25% intracolonic mustard oil (MO) to induce colonic hyperalgesia. The a2d ligand pregabalin effectively reduced the evoked VMR in naïve and MO rats. Moreover, singleunit recordings of RVM ON-, OFF and NEUTRAL-cells were captured using stereotaxic techniques, and cells were identified by evoked responses to noxious tail heat and were further characterized by responses to innocuous and noxious CRD. RVM cells were classed by their somatic responses responded to CRD and ONOFFand NEUTRAL-cells were excited, inhibited or unresponsive to CRD. Pregabalin markedly reduced the evoked responses of RVM ON-cells excited by noxious CRD, but did not significantly affect spontaneous ongoing activity. This study illustrates the role of descending facilitatory modulation from the RVM in visceral pain and provides evidence for the antihyperalgesic efficacy of pregabalin in the CRD model on both motor and sensory measures. Supported by the BBSRC and GlaxoSmithKline, UK

711 ANTI-ALLODYNIC ACTIVITY OF TAPENTADOL IN A RAT MODEL OF NEUROPATHIC PAIN DEPENDS ON OPIOID AND NORADRENERGIC, BUT NOT SEROTONERGIC, MECHANISMS

Background: While m-opioid receptor (MOR) agonism and inhibition of noradrenaline (NA) reuptake are well recognized as analgesic principles in neuropathic pain, the efficacy of serotonin (5-HT) reuptake inhibition is less clear. The novel analgesic tapentadol combines MOR agonism and NA reuptake inhibition in a single molecule, but shows only weak 5-HT reuptake inhibition (Tzschentke et al. J Pharmacol Exp Ther. 2007;323[1]:265–276). This study analyzed the contribution of opioid and monoaminergic mechanisms to the activity of tapentadol in experimental neuropathic pain. Methods: Ipsilateral paw withdrawal thresholds were assessed in the rat spinal nerve ligation model of mononeuropathic pain by means of an electronic von Frey filament to determine neuropathic allodynia. Antagonism studies were performed with the MOR antagonist naloxone (1mg/kg ip), the noradrenergic antagonist yohimbine (2.15mg/kg ip), and the serotonergic antagonist ritanserin (0.316mg/kg ip). Results: Tapentadol HCl (10mg/kg iv) showed clear anti-allodynic effects (>75% efficacy). The effect of tapentadol was profoundly blocked by naloxone and yohimbine but not by ritanserin. The suitability of antagonist doses was shown with the MOR agonist morphine HCl (10mg/kg iv), the mixed NA/5-HT reuptake inhibitor venlafaxine (10mg/kg iv), and the NA reuptake inhibitor desipramine (10mg/kg iv). Conclusions: It is concluded that combined activation of MOR and inhibition of NA reuptake, as obtained with tapentadol, is suitable to induce highly efficient anti-allodynia in a model of neuropathic pain. TC, JDV, UJ, and TMT are Grünenthal employees.

Tapentadol: mit zwei Mechanismen in einem Molekül wirksam gegen nozizeptive und neuropathische Schmerzen@@@Tapentadol: with two mechanisms of action in one molecule effective against nociceptive and neuropathic pain: Präklinischer Überblick@@@Preclinical overview

Tapentadol (3-[(1R, 2R)-3-(dimethylamino)-1-ethyl-2-methylpropyl] phenol) is a centrally acting analgesic of a new substance class for the treatment of severe nociceptive and neuropathic pain. Tapentadol combines μ-opioid receptor (MOR) agonism and noradrenaline reuptake inhibition (NRI) in one molecule. Because of the combined mechanisms of action tapentadol offers a broad therapeutic spectrum for nociceptive as well as neuropathic pain. In different animal models its high efficacy was shown in acute nociceptive, acute and chronic inflammatory as well as in chronic neuropathic pain. Using several preclinical approaches it was shown that the noradrenergic component of tapentadol interacts with the opioid component and that both synergistically contribute to the analgesic effect of the substance. In comparison to known drugs with only one of the two modes of action, tapentadol, despite its high potency, has an improved tolerability profile in the relevant animal models, particularly with regard to gastrointestinal and central side effects. Tapentadol acts directly without metabolic activation and without formation of analgesically relevant metabolites. In different interaction studies a low potential for interactions was shown, thus clinically relevant drug-drug interactions are unlikely. Overall, tapentadol provides a safe pharmacodynamic-pharmacokinetic profile.ZusammenfassungTapentadol (3-[(1R, 2R)-3-(Dimethylamino)-1-Äthyl-2-Methylpropyl]-Phenol) ist ein zentral wirksames Analgetikum einer neuen Substanzklasse zur Behandlung starker nozizeptiver und neuropathischer Schmerzen. Tapentadol kombiniert µ-Opioid-Rezeptor (MOR)-Agonismus und Noradrenalin–Wiederaufnahmehemmung (NRI) in einem Molekül. Aufgrund des kombinierten Wirkmechanismus bietet Tapentadol ein breites Wirkspektrum sowohl im nozizeptiven als auch im neuropathischen Schmerz: In verschiedenen Schmerzmodellen am Tier konnte eine starke Wirksamkeit bei akut-nozizeptiven, akut- und chronisch-entzündlichen sowie bei chronisch-neuropathischen Schmerzen gezeigt werden.Mittels verschiedener präklinischer Ansätze konnte belegt werden, dass die noradrenerge Wirkkomponente in Tapentadol mit der opioidergen Komponente interagiert und beide synergistisch zur analgetischen Wirkung der Substanz beitragen. Im Vergleich zu bekannten Substanzen mit nur einem der beiden Wirkmechanismen besitzt Tapentadol in den entsprechenden Tiermodellen, trotz seiner hohen Potenz, ein verbessertes Verträglichkeitsprofil, insbesondere in Bezug auf gastrointestinale und zentralnervöse Nebenwirkungen.Tapentadol wirkt direkt, ohne metabolische Aktivierung und ohne Bildung analgetisch relevanter Metabolite. In verschiedenen Interaktionsstudien konnte ein geringes Interaktionspotenzial nachgewiesen werden, klinisch relevante Wechselwirkungen mit anderen Substanzen sind somit unwahrscheinlich. Insgesamt bietet Tapentadol also ein sicheres pharmakodynamisch-pharmakokinetisches Profil.AbstractTapentadol (3–[(1R, 2R)-3–(dimethylamino)-1-ethyl-2-methylpropyl] phenol) is a centrally acting analgesic of a new substance class for the treatment of severe nociceptive and neuropathic pain. Tapentadol combines μ-opioid receptor (MOR) agonism and noradrenaline reuptake inhibition (NRI) in one molecule. Because of the combined mechanisms of action tapentadol offers a broad therapeutic spectrum for nociceptive as well as neuropathic pain. In different animal models its high efficacy was shown in acute nociceptive, acute and chronic inflammatory as well as in chronic neuropathic pain.Using several preclinical approaches it was shown that the noradrenergic component of tapentadol interacts with the opioid component and that both synergistically contribute to the analgesic effect of the substance. In comparison to known drugs with only one of the two modes of action, tapentadol, despite its high potency, has an improved tolerability profile in the relevant animal models, particularly with regard to gastrointestinal and central side effects.Tapentadol acts directly without metabolic activation and without formation of analgesically relevant metabolites. In different interaction studies a low potential for interactions was shown, thus clinically relevant drug-drug interactions are unlikely. Overall, tapentadol provides a safe pharmacodynamic-pharmacokinetic profile.

363 DISSOCIATION OF ANALGESIC, ANTI-AVERSIVE AND REWARDING EFFECTS OF DIFFERENT CLASSES OF ANALGESICS IN THE RAT

There is considerable evidence that the activation of spinal GABAAand GABAB-receptors are involved in the neurotransmission of inflammatory and neuropathic pain. The study assessed the role of GABAAand GABAB-receptor activation for incision induced mechanical and thermal hyperalgesia. Methods: Rats with intrathecal catheter (IT; n = 68) underwent plantar incision and mechanical withdrawal thresholds (WT, calibrated von Frey filaments) or thermal withdrawal latencies (PWL, Hargreaves Box) were assessed. The animals received an IT administration of the GABAA-agonist muscimol (0.1mg, 0.3mg), GABAB-agonist baclofen (0.1mg, 0.3mg) or vehicle and pain behavior was evaluated again. In separate experiments animals pretreated with the GABAA-antagonist bicuculline (0.3mg) or GABAB-antagonist CGP35348 (30mg) received the corresponding GABAA/B-agonist. Finally, separate animals received IT injection of bicuculline or CGP35348 after incision. Results: IT administration of muscimol and baclofen increased significantly the decreased median WT after incision from 67mN to 176mN and 145mN 60–90min after injection, respectively (p < 0.05 vs. vehicle). Similar, decreased PWL after incision were increased 60–120min after agonist injection (p < 0.05 vs. vehicle). GABAagonist induced antinociception was blocked with pretreatment of the corresponding antagonist (p < 0.05). IT administration of GABAA/B-antagonist did not modify pain behaviors after incision. Conclusion: Spinal administration of GABAAand GABAB-agonists decreased mechanical and thermal hyperalgesia after incision indicating that spinal GABAAand GABAB-receptors are potential targets for the treatment of incisional pain and hyperalgesia. However, because GABA-antagonists did not cause pain behaviors in incised animals we hypothesize that tonic gabaergic inhibition may be important for nociception after other types of tissue injuries but not after incision.