Opioid and noradrenergic contributions of tapentadol in experimental neuropathic pain

Abstract

Tapentadol is a dual action molecule with mu opioid agonist and norepinephrine (NE) reuptake blocking activity that has recently been introduced for the treatment of moderate to severe pain. The effects of intraperitoneal (i.p.) morphine (10 mg/kg), tapentadol (10 or 30 mg/kg) or duloxetine (30 mg/kg), a norepinephrine/serotonin (NE/5HT) reuptake inhibitor, were evaluated in male, Sprague-Dawley rats with spinal nerve ligation (SNL) or sham surgery. Additionally, the effects of these drugs on spinal cerebrospinal fluid (CSF) NE levels were quantified. Response thresholds to von Frey filament stimulation decreased significantly from baseline in SNL, but not sham, operated rats. Duloxetine, tapentadol and morphine produced significant and time-related reversal of tactile hypersensitivity. Duloxetine significantly increased spinal CSF NE levels in both sham and SNL rats and no significant differences were observed in these groups. Tapentadol (10 mg/kg) produced a significant increase in spinal NE levels in SNL, but not in sham, rats. At the higher dose (30 mg/kg), tapentadol produced a significant increase in spinal CSF NE levels in both SNL and sham groups; however, spinal NE levels were elevated for an extended period in the SNL rats. This could be detected 30 min following tapentadol (30 mg/kg) in both sham and SNL groups. Surprisingly, while the dose of morphine studied reversed tactile hypersensitivity in nerve-injured rats, CSF NE levels were significantly reduced in both sham- and SNL rats. The data suggest that tapentadol elicits enhanced elevation in spinal NE levels in a model of experimental neuropathic pain offering a mechanistic correlate to observed clinical efficacy in this pain state.

Effect of the Norepinephrine Transporter (NET) Inhibition on μ-Opioid Receptor (MOR)-Induced Anti-nociception in a Bone Cancer Pain Model

“…In the spinal nerve ligation model, however, NE in the spinal dorsal horn increased 126% 10 days after surgery (37). Furthermore, a recent study showed that systemic administration of tapentadol elevated cerebral spinal fluid NE in sham and spinal nerve ligated animals, and NE remained elevated for 90 min in the spinal nerve ligated animals only, suggesting sensitization of the NE neurons in this model (29). Even though NE was not examined in all related pain models, differences in NE content might influence the level of NE and NET inhibition; in the pSNL, low NE might be insufficient for NE release and leads to less NET inhibition.…”

“…In support of this, it has been reported that a 1 -adrenoceptor, but not a 2 -adrenoceptor, agonists induce motor and autonomic disturbances (27,28). In addition, microdialysis studies have shown that tapentadol and tramadol increase NE release at synapses, whereas morphine decreases basal NE release at spinal and supraspinal sites (3,19,22,29). Although no reports on oxycodone are available, it seems that the contribution of the a 1 -adrenoceptor-mediated pathway to motor function differs between MOR-selective and dual-acting opioids.…”

Synergistic attenuation of chronic pain using mu opioid and cannabinoid receptor 2 agonists

“…Cocaine hydrochloride was administered via the dialysate probe at the end of the experiment as a positive microdialysis placement control by measuring increased dopamine levels in the NAc. Collected dialysate samples were chilled in the presence of an antioxidant and injected into the HPLC for neurochemical analysis (Meske et al, 2013). Immediately following microdialysis, rats were sacrificed and their brains were harvested.…”

Comparative study of the neurotoxicological effects of tramadol and tapentadol in SH-SY5Y cells

“…Indeed, tramadol is the most commonly prescribed opioid and tapentadol use is increasing (Meske et al 2013;Raffa et al 2012). Although tapentadol does not require metabolic activation, tramadol owes most of its analgesic effect to its main active metabolite, O-desmethyltramadol (M1), although the parent compound exhibits some pharmacological activity (Grond and Sablotzki 2004;Hartrick and Rozek 2011).…”