μ-Opioid receptor activation and noradrenaline transport inhibition by tapentadol in rat single locus coeruleus neurons

Abstract

Background and purpose: Tapentadol is a novel analgesic that combines moderate μ-opioid receptor agonism and noradrenaline reuptake inhibition in a single molecule. Both mechanisms of action are involved in producing analgesia; however, the potency and efficacy of tapentadol in individual neurons has not been characterized.

Experimental approach: Whole-cell patch-clamp recordings of G-protein-coupled inwardly rectifying K(+) (KIR 3.x) currents were made from rat locus coeruleus neurons in brain slices to investigate the potency and relative efficacy of tapentadol and compare its intrinsic activity with other clinically used opioids.

Key results: Tapentadol showed agonist activity at μ receptors and was approximately six times less potent than morphine with respect to KIR 3.x current modulation. The intrinsic activity of tapentadol was lower than [Met]enkephalin, morphine and oxycodone, but higher than buprenorphine and pentazocine. Tapentadol inhibited the noradrenaline transporter (NAT) with potency similar to that at μ receptors. The interaction between these two mechanisms of action was additive in individual LC neurons.

Conclusions and implications: Tapentadol displays similar potency for both µ receptor activation and NAT inhibition in functioning neurons. The intrinsic activity of tapentadol at the μ receptor lies between that of buprenorphine and oxycodone, potentially explaining the favourable profile of side effects, related to μ receptors.

Linked articles: This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2.

Keywords: GIRK channels; KIR3.x; locus coeruleus; noradrenalin reuptake inhibitor; opioid receptor agonist; tapentadol.

Figure 1

K_IR3.x currents induced by activation of μ receptors in LC neurons. Superfusion (shown by bars) of tapentadol (A), morphine (B) and [Met]enkephalin (ME; C) activate K_IR3.x currents at holding potential (−60 mV) in the presence of the α₂-adrenoceptor antagonist, idazoxan. All actions are reversed by the μ receptor antagonist, naloxone. (D) Concentration-response curves for [Met]enkephalin, morphine and tapentadol. The amplitude of the hyperpolarization plotted as a percentage of the amplitude of a supramaximal concentration of UK14304 (UK).

Figure 2

Intrinsic activity of tapentadol at μ receptors (adrenoceptors were blocked from A to F with idazoxan, 1 μM and prazosin 300 nM). (A) Morphine (30 μM) reversibly antagonized the current induced by a supramaximal (and desensitized) concentration of [Met]enkephalin (ME) confirming the lower intrinsic activity of morphine. (B) Tapentadol had lower intrinsic activity than [Met]enkephalin and reversibly antagonized the current induced by a supramaximal (desensitized) concentration of [Met]enkephalin (C) Tapentadol partially and reversibly reduced the current induced by a supramaximal concentration of morphine. (D) Tapentadol partially reduced the current induced by a supramaximal concentration of oxycodone. (E) Buprenorphine and (F) pentazocine almost completely antagonized currents induced by a supramaximal concentration of tapentadol. (G) Tapentadol did not inhibit the current induced by supramaximal concentration of UK14304 (UK) in the presence of naloxone.

Figure 3

Tapentadol potentiates responses of LC neurons to noradrenaline. (A). Typical recording showing that tapentadol in the continuous presence of noradrenaline enhances the outward current induced by noradrenaline (I_NA) via inhibiting the noradrenaline reuptake transporter (NAT). In these experiments, the μ receptors were blocked by naloxone (1 μM). (B). Concentration-response curve for enhancement of the noradrenaline current (I_NA) by tapentadol (IC₅₀ = 2.3 μM).

Figure 4

(A) Tapentadol with combined mode of action enhanced the effects of noradrenaline in single LC neurons. All data were normalized by the maximum effect induced by UK14304 (UK; 3 μM). (B) Comparison between the concentration-response curve of tapentadol as a μ receptor (MOPr) agonist alone (with adrenoceptors blocked; data from Figure 1), tapentadol as a NAT inhibitor alone (with μ receptors blocked; data from Figure 3) and tapentadol acting on both mechanisms in the absence of both μ receptor and α₂-adrenoceptor antagonists.