Biphalin preferentially recruits peripheral opioid receptors to facilitate analgesia in a mouse model of cancer pain - A comparison with morphine.
The search for new drugs for cancer pain management has been a long-standing goal in basic and clinical research. Classical opioid drugs exert their primary antinociceptive effect upon activating opioid receptors located in the central nervous system. A substantial body of evidence points to the relevance of peripheral opioid receptors as potential targets for cancer pain treatment. Peptides showing limited blood-brain-barrier permeability promote peripheral analgesia in many pain models. In the present study we examined the peripheral and central analgesic effect of intravenously administered biphalin - a dimeric opioid peptide in a mouse skin cancer pain model, developed by an intraplantar inoculation of B16F0 melanoma cells. The effect of biphalin was compared with morphine - a golden standard in cancer pain management. Biphalin produced profound, dose-dependent and naloxone sensitive spinal analgesia. Additionally, the effect in the tumor-bearing paw was largely mediated by peripheral opioid receptors, as it was readily attenuated by the blood-brain-barrier-restricted opioid receptor antagonist - naloxone methiodide. On the contrary, morphine facilitated its analgesic effect primarily by activating spinal opioid receptors. Both drugs induced tolerance in B16F0 - implanted paws after chronic treatment, however biphalin as opposed to morphine, showed little decrease in its activity at the spinal level. Our results indicate that biphalin may be considered a future alternative drug in cancer pain treatment due to an enhanced local analgesic activity as well as lower tolerance liability compared with morphine.
Mossakowski Medical Research Centre Polish Academy of Sciences, Pawinskiego 5, 02-106 Warsaw, Poland; Medical University of Warsaw, Department of Pharmacodynamics, Centre for Preclinical Research and Technology, Banacha 1B, 02-097 Warsaw, Poland. Electronic address: alesniak.imdik@gmail.com.
Anna
A
Lesniak
Mossakowski Medical Research Centre Polish Academy of Sciences, Pawinskiego 5, 02-106 Warsaw, Poland. Electronic address: Marta.bochynska@interia.pl.
Marta
M
Bochynska-Czyz
Institute of Genetics and Animal Breeding Polish Academy of Sciences, Postepu 36A, 05-552 Magdalenka, Poland; Medical University of Warsaw, Department of Internal Medicine, Hypertension and Vascular Diseases, Banacha 1A, 02-097 Warsaw, Poland.. Electronic address: m.sacharczuk@ighz.pl.
Mariusz
M
Sacharczuk
Biological Research Centre, Hungarian Academy of Sciences, Temesvari korut, 62 6726 Szeged, Hungary.
Sandor
S
Benhye
Mossakowski Medical Research Centre Polish Academy of Sciences, Pawinskiego 5, 02-106 Warsaw, Poland. Electronic address: misicka@chem.uw.edu.pl.
Aleksandra
A
Misicka
Medical University of Warsaw, Department of Pharmacodynamics, Centre for Preclinical Research and Technology, Banacha 1B, 02-097 Warsaw, Poland. Electronic address: mbujalska@gmail.com.
Magdalena
M
Bujalska-Zadrozny
Mossakowski Medical Research Centre Polish Academy of Sciences, Pawinskiego 5, 02-106 Warsaw, Poland.
Andrzej W
AW
Lipkowski
D000698:Analgesia / Q000379:methods; D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D000072716:Cancer Pain / Q000188:drug therapy* / Q000209:etiology* / Q000378:metabolism; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004361:Drug Tolerance; D004745:Enkephalins / Q000494:pharmacology*; D008297:Male; D008546:Melanoma, Experimental / Q000150:complications / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009020:Morphine / Q000494:pharmacology*; D009270:Naloxone / Q000031:analogs & derivatives / Q000494:pharmacology; D018847:Opioid Peptides / Q000494:pharmacology; D010539:Permeability; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology; D011957:Receptors, Opioid / Q000378:metabolism*; D012878:Skin Neoplasms / Q000150:complications / Q000378:metabolism
D000701:Analgesics, Opioid; D004745:Enkephalins; D018847:Opioid Peptides; D000644:Quaternary Ammonium Compounds; D011957:Receptors, Opioid; D009270:Naloxone; C041269:N-methylnaloxone; D009020:Morphine; C053673:biphalin
Biphalin; Cancer pain; Mouse model; Peripheral analgesia; Tolerance