Semi-mechanistic Modeling of the Interaction Between the Central and Peripheral Effects in the Antinociceptive Response to Lumiracoxib in Rats

Abstract

Abstract. The model-based approach was undertaken to characterize the interaction between the peripheral and central antinociceptive effects exerted by lumiracoxib. The effects of intraplantar and intrathecal administrations and of fixed ratio combinations of lumiracoxib simultaneously administered by these two routes were evaluated using the formalin test in rats. Pain-related behavior data, quantified as the number of flinches of the injected paw, were analyzed using a population approach with NONMEM 7. The pain response during the first phase of the formalin test, which was insensitive to lumiracoxib, was modeled using a monoexponential decay. The second phase, which was sensitive to lumiracoxib, was described incorporating synthesis and degradation processes of pain mediators that were recruited locally after tissue injury. Upregulation at the local level and in the central nervous system (CNS) was set to be proportional to the predicted levels of pain mediators in the local (injured) compartment. Results suggest a greater role of upregulated COX-2 Local in generating the pain response compared to COX-2 CNS . Drug effects were described as inhibition of upregulated COX-2. The model adequately described the time course of nociception after formalin injection in the absence or presence of lumiracoxib administered locally and/or spinally. Data suggest that the overall response is the additive outcome of drug effects at the peripheral and central compartments, with predominance of peripheral mechanisms. Application of modeling opens new perspectives for understanding the overall mechanism of action of analgesic drugs.

Isobolographic analysis of antinociceptive effect of ketorolac, indomethacin, and paracetamol after simultaneous peripheral local and systemic administration

“…In this regard, oral and spinal co-administration of diclofenac produced an additive interaction (Ortiz et al ., 2008), while the intraperitoneal and intraplantar co-administration of tramadol, produced a self-synergistic antinociceptive effect (Pozos-Guillén et al ., 2006). Furthermore, it has been proposed that the antinociceptive effect after intraplantar and intrathecal co-administration of lumiracoxib is additive (Vélez de Mendizábal et al ., 2012) in the formalin test. In the present study, although the mechanisms underlying the additive effect of ketorolac or paracetamol and the self-synergism of indomethacin were not explored, it is likely that the above-cited peripheral and central mechanism dependent and independent of COX inhibition are involved.…”

Activation of Peripheral Cannabinoid Receptors Synergizes the Effect of Systemic Ibuprofen in a Pain Model in Rat

“…Additionally, a self-synergism was reported with WIN 55,212-2 administered in two different routes, the intrathecal and intraplantar [ 4 ]. However, other studies have only shown an additive effect [ 5 ], or there was no change in the antinociceptive effect with the administration of tramadol by two different routes [ 6 ].…”