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

Abstract

Tapentadol is a m-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 (0.1-3.16 mg/animal) showed full efficacy after intrathecal as well as after intracerebroventricular administration (ED 50 0.42 mg/animal i.t., 0.18 mg/animal i.c.v.). Combined administration of equianalgesic doses revealed spinal-supraspinal synergy (ED 50 0.053 mg/animal i.t. 1 i.c.v.). Morphine (0.001-10 mg/animal) also showed central efficacy and synergy (ED 50 0.547 mg/animal i.t., 0.004 mg/animal i.c.v., 0.014 mg/animal i.t. 1 i.c.v.). Supraspinal potencies of tapentadol and morphine correlated with the 50-fold difference in their MOR affinities. In contrast, spinal potencies of both drugs were similar and correlated with their relative systemic potencies (ED 50 0.27 mg/kg i.p. tapentadol, 1.1 mg/kg i.p. morphine). Spinal administration of the opioid antagonist naloxone or the a 2 -adrenoceptor antagonist yohimbine before systemic administration of equianalgesic doses of tapentadol (1 mg/kg i.p.) or morphine (3.16 mg/kg i.p.) revealed pronounced influence on opioidergic and noradrenergic pathways for both compounds. Tapentadol was more sensitive toward both antagonists than was morphine, with median effective dose values of 0.75 and 1.72 ng/animal i.t. naloxone and 1.56 and 2.04 ng/animal i.t. yohimbine, respectively. It is suggested that the antihyperalgesic action of systemically administered tapentadol is based on opioid spinal-supraspinal synergy, as well as intrinsic spinally mediated MOR-NRI synergy.

Diabetic neuropathic pain: Physiopathology and treatment

“…In line with this idea, new molecules that integrate additional mechanisms to the opioid receptor agonism have been shown efficacy in reducing nociceptive behavior in animal models of DNP, such as the cebranopadol, a nociceptin/orphanin FQ peptide and opioid receptor agonist [166] , and the mu opioid receptor agonist and norepinephrine reuptake inhibitor, tapentadol [162,167] . The latter was approved by FDA for DNP treatment since 2012 [11] .…”

Treatment of painful diabetic neuropathy

“…Tapentadol ER was administered to 588 patients for a 3-week open-label phase, and subsequently, 395 patients with at least a one-point reduction in pain intensity were randomized 1:1 to receive placebo or the optimal fixed dose of tapentadol ER for a 12-week double-blind phase to show a highly significant reduction in pain intensity for those on active treatment [Schwartz et al 2011]. The mechanism of action is thought to be via opioid spinal-supraspinal synergy, as well as intrinsic spinally mediated μ-opioid receptor agonist-norepinephrine reuptake inhibitor effect [Christoph et al 2013]. The other opioid that has been studied in PDN is oxycodone, which has higher bioavailability and potency compared with morphine and a reduced side-effect profile.…”

Treating Diabetic Neuropathy: Present Strategies and Emerging Solutions

“…Patients in the tapentadol arm of this trial reported a significant reduction in pain intensity compared with placebo. It has been proposed that tapentadol suppresses neuropathic pain through opioid spinal-supraspinal synergy in addition to the µ-opioid agonist and norepinephrine inhibitory effect [124].…”