Effect of tapentadol on neurons in the locus coeruleus

Tapentadol is a novel centrally acting drug that combines mu-opioid receptor (MOR) agonism and noradrenaline reuptake inhibition (NRI), producing analgesic effects in various painful conditions. We investigated the acute effects of tapentadol in the locus coeruleus (LC), a central nucleus regulated by the noradrenergic and opioid systems that is critical in pain modulation. In single-unit extracellular recordings of LC neurons from anaesthetized male SpragueeDawley rats, tapentadol clearly inhibited the spontaneous electrophysiological activity of LC neurons in a dose-dependent manner (ED50 ¼ 0.8 mg/kg). This inhibitory effect was reversed by RX821002 (an alpha2-adrenoceptor antagonist) and naloxone (a mu-opioid receptor antagonist) by 96.7% and 28.2%, respectively. Pretreatment with RX821002, Nethoxycarbonyl- 2-ethoxy-1-2-dihydroquinoline (EEDQ, an irreversible alpha2-adrenoceptor antagonist) or naloxone shifted the tapentadol doseeeffect curve to the right (ED50 ¼ 2.2 mg/kg, 2.0 mg/kg and 2.1 mg/kg, respectively). Furthermore, tapentadol inhibited the LC response to mechanical stimulation of the hindpaw in a dose-dependent manner. In summary, we demonstrate that acute administration of tapentadol inhibits LC neurons in vivo, mainly due to the activation of alpha2-adrenoceptors. These data suggest that both the noradrenergic and opioid systems participate in the inhibitory effect of tapentadol on LC neurons, albeit to different extents, which may account for its potent analgesic effect and mild opioidergic side-effects.This study was supported by grants from Grünenthal GmbH (OT2010/075); “Fondo de Investigación Sanitaria” (PI10/01221 and PI12/00915); CIBERSAM (G18); Junta de Andalucía, Consejería de Innovación, Ciencia y Empresa (CTS-510, CTS-4303 and CTS-7748); Cátedra Externa del Dolor Grünenthal-Universidad de Cádiz; FP7-PEOPLE-2010-RG (268377); FPU (AP2007-02397) and FPI (2011-145) fellowship

al Atsaru al Siyasiy Lil'ulama` fi Ashri al Murabithin

314 hlm., 24 cm

Rilmenidine reveals differences in the pharmacological characteristics of prejunctional α(2)-adrenoceptors in the guinea-pig, rat and pig

1. The α(2A) and α(2D)-adrenoceptor subtypes are thought to be species homologs most easily differentiated on the basis of the potency of antagonists. In the present study we have compared the effect of rilmenidine with two other selective α(2)-adrenoceptor agonists, UK-14304 (5-bromo-6- [2-imidazolin-2-ylamino]-quinoxaline) and clonidine, against electrically-evoked contractions in five isolated preparations from the rat, guinea-pig and pig, and, where possible, determined the receptor subtype involved. 2. UK-14034, clonidine and rilmenidine produced concentration-dependent inhibition of the electrically-evoked contractions of the rat isolated vas deferens and tail artery and the guinea-pig ileum. These inhibitory effects were reversed by the selective α(2)-adrenoceptor antagonist, RX-811058 (1 μM), except in the rat tail artery preparations where the remaining neurogenic response was inhibited; evidence for the involvement of `innervated' α(2)-adrenoceptors. Both clonidine and UK-14304 produced concentration-dependent inhibition of responses in the porcine isolated tail artery and urinary bladder but clonidine was markedly less efficacious in these preparations. In contrast, rilmenidine failed to inhibit the neurogenic contractions in either preparation. 3. Although rilmenidine failed to elicit a detectable response in either the porcine isolated tail artery or urinary bladder, it (10 μM and 30 μM, respectively) competitively antagonised the inhibitory effects of UK-14304 with an estimated dissociation constant of (pK(B)) 5.82 and 5.93, respectively. 4. Prazosin (1 μM) failed to alter the effect of UK-14304 against neurogenic contractions in the porcine isolated urinary bladder, while rauwolscine (pK(B) 8.87) was 10 fold more potent than phentolamine (pK(B) 7.56). On the other hand, phentolamine (pK(B) 8.42) was only marginally more potent than rauwolscine (pK 8.05) against clonidine-induced inhibition of electrically-evoked contractions of the guinea-pig isolated ileum. This pharmacological evidence with antagonists supports the presence of α(2D)-adrenoceptors in the rat and guinea-pig and the α(2A)-adrenoceptors in the pig. 5. We have demonstrated that rilmenidine, unlike clonidine and UK-14304, is devoid of any agonist activity at prejunctional α(2A)-adrenoceptors in the pig, but is an efficacious agonist at α(2D)-adrenoceptors in the rat and guinea-pig

Opioid and noradrenergic contributions of tapentadol to the inhibition of locus coeruleus neurons in the streptozotocin rat model of polyneuropathic pain

International audienceTapentadol is an analgesic that acts as an agonist of µ opioid receptors (MOR) and that inhibits noradrenaline reuptake. Data from healthy rats show that tapentadol inhibits neuronal activity in the locus coeruleus (LC), a nucleus regulated by both the noradrenergic and opioid systems. Thus, we set out to investigate the effect of tapentadol on LC activity in streptozotocin (STZ)-induced diabetic rats, a model of diabetic polyneuropathy, by analyzing single-unit extracellular recordings of LC neurons. Four weeks after inducing diabetes, tapentadol dose-response curves were obtained from animals pre-treated with RX821002 or naloxone (alpha2-adrenoceptors and opioid receptors antagonists, respectively). In STZ rats, the spontaneous activity of LC neurons (0.9 ± 0.1 Hz) was lower than in naïve animals (1.5 ± 0.1 Hz), and tapentadol's inhibitory effect was also weaker. Alpha2-adrenoceptors blockade by RX821002 (100 μg/kg i.v.) in STZ animals significantly increased the spontaneous activity (from 0.8 ± 0.1 to 1.4 ± 0.2 Hz) and it dampened the inhibition of LC neurons produced by tapentadol. However, opioid receptors blockade following naloxone pre-treatment (5 mg/kg i.v.) did not alter the spontaneous firing rate (0.9 ± 0.2 vs 0.9 ± 0.2 Hz) or the inhibitory effect of tapentadol on LC neurons in STZ animals. Thus, diabetic polyneuropathy appears to exert neuroplastic changes in LC neurotransmission, enhancing the sensitivity of alpha2-adrenoceptors and dampening opioid receptors expression. Tapentadol's activity seems to be predominantly mediated through its noradrenergic effects rather than its influence on opioid receptors in the STZ model of diabetic polyneuropathy