Mihály Balogh1, Ferenc Zádor2, Zoltán S. Zádori1, Shaqura Mohammed3, Kornél Király1, Amir Mohammadzadeh1, Bence Varga1, Dávid Karádi1, Bernadette Lázár1, Shaaban A. Mousa3, Sándor Hosztafi4, Pál Riba1, Sándor Benyhe2, Michael Schäfer3, Susanna Fürst1, Mahmoud Al-Khrasani1
1 Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, Budapest, Hungary
2 Institute of Biochemistry, Biological Research Center of the Hungarian Academy of Sciences, Szeged, Hungary
3 Department of Anaesthesiology and Intensive Care Medicine, Charité University Berlin, Campus Virchow Klinikum and Campus Charite Mitte, Berlin, Germany
4 Department of Pharmaceutical Chemistry, Semmelweis University, Budapest, Hungary
The analgesic action of opioids in diabetic neuropathic pain (DNP) is impaired due to reduction in opioid receptor reserve. Therefore, high efficacy opioids having spare receptors may be promising analgesics.
Aims: 1) Examination of the antiallodynic effect of a novel high efficacy opioid agonist, 14-O-methymorphine-6-O-sulfate (14-O-MeM6SU) in comparison with fentanyl and morphine in rats with DNP, after systemic administration. 2) Determination of the degree of antinociception impairment. 3) Investigation of the peripheral component in the antinociceptive actions. 4) To further analyze the actions of test opioid agonists at spinal and supraspinal level applying biochemical assays.
Methods: Diabetic polyneuropathy was induced by ip. streptozocin (STZ) injection in male Wistar rats (200-250 g). Mechanical allodynia was weekly assessed by dynamic plantar aesthesiometer until 12 weeks after STZ injection. Experiments were performed at the 9th week. The role of peripheral opioid receptors in antinociception was investigated by the co-administration of naloxon methiodide (NAL-M, opioid antagonist with limited CNS penetration). For in vitro analysis G-protein functioning and immunohistological assays were performed.
Results: 14-O-MeM6SU and fentanyl displayed similar antinociception in diabetic and non-diabetic rats. However, a 7-times impairment in morphine antinociception was measured. NAL-M failed to alter the antiallodynic effect of test compounds, indicating the contribution of central opioid receptors. Significant impairment in G-protein coupling was measured for morphine, yet no change in case of 14-O-MeM6SU or fentanyl at spinal level of diabetic- and non-diabetic animals. Furthermore, reduction in MOR immunoreactivity of nerve terminals was detected in the spinal cord and dorsal root ganglia of diabetic rats.
Conclusion: The reduction of spinal opioid receptors concomitant with reduced analgesic effect of morphine may be circumvented by prescribing high efficacy opioids, which provide superior analgesia over morphine.
Doctoral School: Pharmaceutical Sciences
Program: Experimental and Clinical Pharmacology
Supervisor: Mahmoud Al-Khrasani
E-mail address: email@example.com