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

Abstract

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. Antihypersensitive efficacy was inferred from ipsilateral paw withdrawal thresholds toward an electronic von Frey filament in a spinal nerve ligation model of mononeuropathic pain. Dose-response curves of tapentadol (intravenous) were determined in combination with vehicle or a fixed dose (intraperitoneal) of the mu-opioid receptor antagonist naloxone (1mg/kg), the alpha2-adrenoceptor antagonist yohimbine (2.15 mg/kg), or the serotonin 5-HT(2A) receptor antagonist ritanserin (0.316 mg/kg). Tapentadol showed clear antinociceptive and antihypersensitive effects (>90% efficacy) with median effective dose (ED(50)) values of 3.3 and 1.9 mg/kg, respectively. While the antinociceptive ED(50) value of tapentadol was shifted to the right 6.4-fold by naloxone (21.2mg/kg) and only 1.7-fold by yohimbine (5.6 mg/kg), the antihypersensitive ED(50) value was shifted to the right 4.7-fold by yohimbine (8.9 mg/kg) and only 2.7-fold by naloxone (5.2mg/kg). Ritanserin did not affect antinociceptive or antihypersensitive ED(50) values of tapentadol. Activation of both mu-opioid receptors and alpha2-adrenoceptors contribute to the analgesic effects of tapentadol. The relative contribution is, however, dependent on the particular pain indication, as mu-opioid receptor agonism predominantly mediates tapentadol's antinociceptive effects, whereas noradrenaline reuptake inhibition predominantly mediates its antihypersensitive effects.

Synergistic Interaction between the Two Mechanisms of Action of Tapentadol in Analgesia

“…2A. It is evident from these relationships that tapentadol's MOR-mediated action was more potent than that caused by NRI in this test (Schröder et al, 2010). It is also seen (Fig.…”

“…that produced complete antagonism of a maximally effective dose of the reference agonist reboxetine in both the low-intensity tail-flick test and the SNL model was used to compare the relative contribution of the NRI component to the effect of tapentadol in these two models (Schröder et al, 2010). In the second set of experiments involving intraperitoneal tapentadol administration in the low-intensity tailflick test, the dose of yohimbine was further increased to a maximum of 4.64 mg/kg i.p.…”

“…Because mechanical hypersensitivity testing in the SNL model lasted approximately 5 min, whereas testing in the tail-flick assay was performed instantaneously, the administration time point of the antagonists relative to the agonists was adapted jpet.aspetjournals.org accordingly in the SNL model. Antagonist drug doses were carefully chosen to reach full antagonism of a maximally active dose of respective reference agonists (morphine, reboxetine) without confounding analgesic effect or behavioral side effects (Schröder et al, 2010). All doses refer to the respective salt form as indicated above.…”

Uso do exercício resistido antagonizado por naloxone como fator de analgesia em sinovite aguda de joelho de ratos Wistar

“…Picard et al 12 reported that there is no evidence of the role of opioids in the peripheral analgesia for acute pain; however, it is worth mentioning that they did not evaluate the role of opioid drugs of intra-articular action, being different from the present study which tried to evaluate the antinociceptive effect of exercise and whether it could occur via peripherally and intra-articular opioid, since the naloxone injection followed different dose and via recommended for systemic action [13][14][15] . Sensitization of articular primary afferent nociceptors (peripheral sensitization) and of neurons of the spinal cord (central sensitization) are basic neuronal processes in pain and mechanical hyperalgesia.…”

Spinal-Supraspinal and Intrinsicµ-Opioid Receptor Agonist-Norepinephrine Reuptake Inhibitor (MOR-NRI) Synergy of Tapentadol in Diabetic Heat Hyperalgesia in Mice

“…The MOR affinity of tapentadol is 50-fold lower than that of morphine (Tzschentke et al, 2007), whereas the potency in the spinal nerve ligation model in rats and in diabetic hyperalgesia in mice was shown to be in the same range as that of morphine Schröder et al, 2010). This shift in potency in vivo compared with MOR affinity in vitro is thought to be attributed to the NRI component of tapentadol, which was shown to contribute more to the antihypersensitive effect in spinal nerve-ligated rats than to the antinociceptive effect in naïve rats (Schröder et al, 2010). Furthermore, isobolographic analysis suggests an intrinsic synergism of the two mechanisms of action of tapentadol in nociceptive and neuropathic pain conditions in rats (Schröder et al, 2011).…”