TOLPERISONE-PREGABALIN-BASED APPROACH FOR NEUROPATHIC PAIN MANAGEMENT AND MORPHINE TOLERANCE
Nariman Essmat Mohamed Abdeltawab Gomaa
Gyógyszertudományok és Egészségügyi Technológiák Tagozat
Dr. Zelkó Romána
SE Farmakológiai és Farmakoterápiás Intézet Knoll József terem
2025-08-21 14:00:00
Experimental and Clinical Pharmacology
Dr. Szökő Éva
Dr. Al-Khrasani Mahmoud
Dr. Papp Noémi
Dr. Zupkő István
Dr. Zelkó Romána
Dr. Mészáros Ágnes Andrea
Dr. Juhász Gabriella
Dr. Lekli István
Two different pain models for NP, rat mono-neuropathic and polyneuropathic pains evoked by pSNL and STZ, respectively, were used. Tactile allodynia, which is the cardinal sign of NP, was assessed by DPA. TOLP and PGB produced an antiallodynic effect after 2 weeks of chronic treatment in rats with mono-neuropathic pain at 100 mg/kg and 50 mg/kg, respectively. As a novel finding, a combination of TOLP/PGB at the sub-antiallodynic doses (both at 25 mg/kg) has shown an acute anti-tactile allodynic effect of fast onset in the rat mono-neuropathic pain. Enhanced glutamate content in the CSF of neuropathic rats was measured. This elevation in glutamate contents was restored by the administration of either TOLP, PGB, or their combination. Likewise, except for PGB, this treatment strategy was able to decrease the glutamate release in vitro in the rat brain synaptosomes. The TOLP/PGB combination, which was proven to be effective against mono-neuropathic pain, was unable to reverse the established allodynia in rats with diabetic polyneuropathic pain under the current experimental conditions. However, only PGB per se caused a significant anti-tactile allodynic effect associated with an increase in the MOR level in the spinal tissue of treated rats. Morph antinociceptive tolerance was induced by chronic Morph treatments. Rats subjected to simultaneous treatment with Morph and PGB but not with TOLP have shown a delay in the development of Morph antinociceptive tolerance. D-serine level was low in the CSF samples of rats receiving chronic Morph/PGB but not TOLP/Morph combination. To avoid the systemic metabolism and interaction between the combined drugs, the possible mechanism of the interaction between TOLP and PGB or Morph was further investigated in the MVD assay. Combining TOLP with PGB, but not Morph, resulted in an augmented inhibitory effect in MVD muscle contraction evoked by field electrical stimulation. MVD treated with three subsequent Morph administrations has shown tolerance to Morph inhibitory effect. In this study, the development of Morph tolerance was inhibited by co-treatment with either PGB or TOLP. When comparing the in vitro and in vivo data, pharmacokinetic parameters may have an impact on the reported effects of TOLP with regard to Morph tolerance, which further urges more research. Finally, considering the side effects, the combination of TOLP/PGB has demonstrated significant promise in rat motor performance and GI transit.
