Acamprosate effect on neuropathic pain in rats: With emphasis on the role of ERK/MAPK pathway and SCN9A sodium channel.

BACKGROUND: Neuropathic pain is a chronic pain owing to nerve damage or diseases of the central nervous system (CNS). The expression of SCN9A, which encodes the Nav1.7 voltage-gated sodium channel and ERK have been found to change significantly in many cases of neuropathic pain. Here, we investigated effects of acamprosate on neuropathic pain, taking into account the crucial roles of SCN9A, the ERK signaling pathway, and inflammatory markers in a rat model of chronic constriction injury (CCI). METHODS: Acamprosate (300 mg/kg) was injected intraperitoneally (i.p.) for 14 days. The tail-immersion, acetone, and formalin tests were used to determine behavioral tests such as heat allodynia, cold allodynia, and chemical hyperalgesia, respectively. Lumbar spinal cord was extracted and processed for Nissl staining. The amount of spinal SCN9A expression and ERK phosphorylation were examined using ELISA assay. RESULTS: The expression of SCN9A, ERK, inflammatory cytokines (IL-6 and TNF-α), allodynia and hyperalgesia significantly increased on days 7 and 14 following CCI. The treatment not only reduced neuropathic pain but also blocked CCI's effects on SCN9A upregulation and ERK phosphorylation. CONCLUSION: This research demonstrated that acamprosate reduces the neuropathic pain induced by CCI of the sciatic nerve in rats by preventing cell loss, inhibiting spinal SCN9A expression, ERK phosphorylation, and inflammatory cytokines, suggesting potential therapeutic implications of acamprosate administration for the treatment of neuropathic pain.

The Permeation of Acamprosate Is Predominantly Caused by Paracellular Diffusion across Caco-2 Cell Monolayers: A Paracellular Modeling Approach.

In drug development, estimating fraction absorbed (Fa) in man for permeability-limited compounds is important but challenging. To model Fa of such compounds from apparent permeabilities (Papp) across filter-grown Caco-2 cell monolayers, it is central to elucidate the intestinal permeation mechanism(s) of the compound. The present study aims to refine a computational permeability model to investigate the relative contribution of paracellular and transcellular routes to the Papp across Caco-2 monolayers of the permeability-limited compound acamprosate having a bioavailability of ∼11%. The Papp values of acamprosate and of several paracellular marker molecules were measured. These Papp values were used to refine system-specific parameters of the Caco-2 monolayers, that is, paracellular pore radius, pore capacity, and potential drop. The refined parameters were subsequently used as an input in modeling the permeability (Pmodeled) of the tested compounds using mathematical models collected from two published permeability models. The experimental data show that acamprosate Papp across Caco-2 monolayers is low and similar in both transport directions. The obtained acamprosate Papp, 1.56 ± 0.28 × 10-7 cm·s-1, is similar to the Papp of molecular markers for paracellular permeability, namely, mannitol (2.72 ± 0.24 × 10-7 cm·s-1), lucifer yellow (1.80 ± 0.35 × 10-7 cm·s-1), and fluorescein (2.10 ± 0.28 × 10-7 cm·s-1), and lower than that of atenolol (7.32 ± 0.60 × 10-7 cm·s-1; mean ± SEM, n = 3-6), while the end-point amount of acamprosate internalized by the cell monolayer, Qmonolayer, was lower than that of mannitol. Acamprosate did not influence the barrier function of the monolayers since it altered neither the Papp of the three paracellular markers nor the transepithelial electrical resistance (TEER) of the cell monolayer. The Pmodeled for all the paracellular markers and acamprosate was dominated by the Ppara component and matched the experimentally obtained Papp. Furthermore, acamprosate did not inhibit the uptake of probe substrates for solute carriers PEPT1, TAUT, PAT1, EAAT1, B0,+AT/rBAT, OATP2B1, and ASBT expressed in Caco-2 cells. Thus, the Pmodeled estimated well Ppara, and the paracellular route appears to be the predominant mechanism for acamprosate Papp across Caco-2 monolayers, while the alternative transcellular routes, mediated by passive diffusion or carriers, are suggested to only play insignificant roles.