Antinociceptive and antihyperalgesic effects of tapentadol in animal models of inflammatory pain.

The novel analgesic tapentadol HCl [(-)-(1R,2R)-3-(3-dimethylamino)-1-ethyl-2-methyl-propyl)-phenol hydrochloride] combines µ-opioid receptor (MOR) agonism and noradrenaline reuptake inhibition (NRI) in a single molecule and shows a broad efficacy profile in various preclinical pain models. This study analyzed the analgesic activity of tapentadol in experimental inflammatory pain. Analgesia was evaluated in the formalin test (pain behavior, rat and mouse), carrageenan-induced mechanical hyperalgesia (paw-pressure test, rat), complete Freund's adjuvant (CFA)-induced paw inflammation (tactile hyperalgesia, rat), and CFA knee-joint arthritis (weight bearing, rat). Tapentadol showed antinociceptive activity in the rat and mouse formalin test with an efficacy of 88 and 86% and ED(50) values of 9.7 and 11.3 mg/kg i.p., respectively. Tapentadol reduced mechanical hyperalgesia in carrageenan-induced acute inflammatory pain by 84% with an ED(50) of 1.9 mg/kg i.v. In CFA-induced tactile hyperalgesia, tapentadol showed 71% efficacy with an ED(50) of 9.8 mg/kg i.p. The decrease in weight bearing after CFA injection in one knee joint was reversed by tapentadol by 51% with an ED(25) of 0.9 mg/kg i.v. Antagonism studies were performed with the MOR antagonist naloxone and the α(2)-noradrenergic receptor antagonist yohimbine in the carrageenan- and CFA-induced hyperalgesia model. In the CFA model, the serotonergic receptor antagonist ritanserin was also tested. The effect of tapentadol was partially blocked by naloxone and yohimbine and completely blocked by the combination of both, but it was not affected by ritanserin. In summary, tapentadol showed antinococeptive/antihyperalgesic analgesic activity in each model of acute and chronic inflammatory pain, and the antagonism experiments suggest that both MOR activation and NRI contribute to its analgesic effects.

Tapentadol hydrochloride: a next-generation, centrally acting analgesic with two mechanisms of action in a single molecule.

Tapentadol exerts its analgesic effects through micro opioid receptor agonism and noradrenaline reuptake inhibition in the central nervous system. Preclinical studies demonstrated that tapentadol is effective in a broad range of pain models, including nociceptive, inflammatory, visceral, mono- and polyneuropathic models. Moreover, clinical studies showed that tapentadol effectively relieves moderate to severe pain in various pain care settings. In addition, it was reported to be associated with significantly fewer treatment discontinuations due to a significantly lower incidence of gastrointestinal-related adverse events compared with equivalent doses of oxycodone. The combination of these reduced treatment discontinuation rates and tapentadol efficacy for the relief of moderate to severe nociceptive and neuropathic pain may offer an improvement in pain therapy by increasing patient compliance with their treatment regimen.

BAY 38-7271: a novel highly selective and highly potent cannabinoid receptor agonist for the treatment of traumatic brain injury.

Traumatic brain injury (TBI) is the most common cause of mortality and morbidity in adults under 40 years of age in industrialized countries. Worldwide the incidence is increasing, about 9.5 million people are hospitalized per year due to TBI, and the death rate is estimated to be more than one million people per year. Recently BAY 38-7271 has been characterized as a structurally novel, selective and highly potent cannabinoid CB1/CB2 receptor agonist in vitro and in vivo with pronounced neuroprotective efficacy in a rat traumatic brain injury model, showing a therapeutic window of at least 5 h. Furthermore, neuroprotective efficacy was also found in models of transient and permanent occlusion of the middle cerebral artery and brain edema models as well. In this article we review the in vitro and in vivo pharmacology of BAY 38-7271, the results from acute and subacute toxicity studies, pharmacokinetics and drug metabolism in animals and healthy male volunteers. In phase I studies BAY 38-7271 was safe and well tolerated when administered by i.v. infusion for either 1 or 24 h. As the doses of BAY 38-7271 in animals needed for maximal neuroprotective efficacy were significantly lower than those inducing typical cannabinoid-like side effects, it is to be expected that the compound will offer a novel therapeutic approach with a favorable therapeutic window for the treatment of TBI or cerebral ischemia.

Effects of alpha 4/beta 2- and alpha 7-nicotine acetylcholine receptor agonists on prepulse inhibition of the acoustic startle response in rats and mice.

RATIONALE: Nicotine and agonists at subtypes of the nicotine acetylcholine receptor (nAChR) affect auditory gating, but the magnitude and direction of such effects appear highly variable. This variability may be due to differences in the tested dose range, selectivity of the test compound, species and strain, and suggests that nAChR subtypes are differentially involved in the control of auditory gating. OBJECTIVES AND METHODS: This study aimed to characterise the effects of nicotine and agonists with preferential activity at alpha4/beta2- and alpha7-nAChRs on auditory sensorimotor gating using a prepulse inhibition (PPI) paradigm. Similar experimental conditions were employed in rats and two strains of mice. The paradigm used startle stimuli of 120 dB and prepulse intensities of 3, 6 and 12 dB above a background of 70 dB. RESULTS: In Sprague-Dawley rats, nicotine disrupted PPI [minimal effective dose (MED): 1 mg/kg, SC] and this effect was mimicked by the potent nAChR agonist, epibatidine, (MED: < or = 0.001 mg/kg, IP) and the potent, and relatively selective, alpha4/beta2-nAChR agonist A-85380 (MED: < or = 0.1 mg/kg, IP). The effects of epibatidine, A-85380 and, to a lesser extent, nicotine were blocked by the non-selective nAChR antagonist mecamylamine. The relatively selective alpha7-nAChR agonists, GTS-21 and AR-R-17779, did not affect PPI in a consistent manner, both in rats and in DBA/2 mice, a strain expressing a disrupted gating phenotype, presumably due to altered activity of hippocampal alpha7-nAChRs. In BALB/c mice, a strain expressing a normal gating phenotype, nicotine (MED: 10 mg/kg, SC), epibatidine (MED: 0.03 mg/kg, IP) and A-85380 (MED: 0.3 mg/kg, IP) predominantly augmented PPI and mecamylamine attenuated these effects. CONCLUSIONS: The present results confirm that the effects of nAChR agonists on PPI are species dependent and suggest that stimulation of heteromeric nAChRs containing both alpha and beta subunits, and possibly of the alpha4/beta2 type, affect sensorimotor gating. Evidence supporting a role for alpha7-nAChRs in the control of PPI of the acoustic startle response was not obtained.