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Side-effects of analgesic kyotorphin derivatives: advantages over clinical opioid drugs

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Abstract

The adverse side-effects associated with opioid administration restrain their use as analgesic drugs and call for new solutions to treat pain. Two kyotorphin derivatives, kyotorphin-amide (KTP–NH2) and ibuprofen–KTP–NH2 (IbKTP–NH2) are promising alternatives to opioids: they trigger analgesia via an indirect opioid mechanism and are highly effective in several pain models following systemic delivery. In vivo side-effects of KTP–NH2 and IbKTP–NH2 are, however, unknown and were evaluated in the present study using male adult Wistar rats. For comparison purposes, morphine and tramadol, two clinically relevant opioids, were also studied. Results showed that KTP-derivatives do not cause constipation after systemic administration, in contrast to morphine. Also, no alterations were observed in blood pressure or in food and water intake, which were only affected by tramadol. A reduction in micturition was detected after KTP–NH2 or tramadol administrations. A moderate locomotion decline was detected after IbKTP–NH2-treatment. The side-effect profile of KTP–NH2 and IbKTP–NH2 support the existence of opioid-based mechanisms in their analgesic actions. The conjugation of a strong analgesic activity with the absence of the major side-effects associated to opioids highlights the potential of both KTP–NH2 and IbKTP–NH2 as advantageous alternatives over current opioids.

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Abbreviations

BBB:

Blood–brain barrier

BP:

Blood pressure

CNS:

Central nervous system

DMSO:

Dimethyl sulfoxide

i.p.:

Intraperitoneal

KTP:

Kyotorphin (Tyr-Arg)

KTP–NH2 :

Kyotorphin–amide

IbKTP–NH2 :

KTP–NH2 linked to ibuprofen

MCs:

Metabolic cages

SBP:

Systolic blood pressure

SEM:

Standard error of the mean

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Acknowledgments

We thank Autonomic Nervous System Unit and Neurosciences Unit from Instituto de Medicina Molecular (Portugal), especially Prof. I. Rocha, Prof. A. Sebastião and Dr. L. Lopes for the support, helpful discussions and facilities provided. Manuel N. Melo is thanked for critical revision of the manuscript. Fundação para a Ciência e Tecnologia (Portugal) is acknowledged for funding: SFRH/BD/42158/2007 fellowship to M. Ribeiro and SFRH/BI/51213/2010 fellowship (for doctorate) to S. Sá Santos associated to Marie Curie IAPP. Marie Curie Industry-Academia Partnerships and Pathways (European Commission) is also acknowledged for funding (FP7-PEOPLE-2007-3-1-IAPP. Project 230654). The authors acknowledge and appreciate the financial support received from Faculdade de Medicina da Universidade de Lisboa and Fundação Amadeu Dias, Portugal (Project No. 2010029).

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Authors and Affiliations

  1. Faculdade de Medicina de Lisboa, Instituto de Medicina Molecular, Av. Professor Egas Moniz, 1649-028, Lisbon, Portugal

    Marta M. B. Ribeiro, Sónia Sá Santos, David S. C. Sousa, Sara M. Santos & Miguel A. R. B. Castanho

  2. Departamento de Biologia Experimental, Faculdade de Medicina do Porto, Rua Dr. Plácido da Costa, no 91, Edifício CIM_FMUP, 4200-450, Porto, Portugal

    Margarida Oliveira & Isaura Tavares

  3. Instituto de Biologia Molecular e Celular, Rua Campo Alegre, 4150-180, Porto, Portugal

    Margarida Oliveira & Isaura Tavares

  4. Laboratori d’Innovació en Processos i Productes de Síntesi Orgànica (LIPPSO), Departament de Química, Universitat de Girona, Campus Montilivi, 17071, Girona, Spain

    Montserrat Heras & Eduard Bardaji

Authors
  1. Marta M. B. Ribeiro
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  2. Sónia Sá Santos
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  3. David S. C. Sousa
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  4. Margarida Oliveira
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  5. Sara M. Santos
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  6. Montserrat Heras
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  7. Eduard Bardaji
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  8. Isaura Tavares
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  9. Miguel A. R. B. Castanho
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Corresponding author

Correspondence to Miguel A. R. B. Castanho.

Additional information

Marta M. B. Ribeiro, Sónia Sá Santos contributed equally to this work.

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Ribeiro, M.M.B., Santos, S.S., Sousa, D.S.C. et al. Side-effects of analgesic kyotorphin derivatives: advantages over clinical opioid drugs. Amino Acids 45, 171–178 (2013). https://doi.org/10.1007/s00726-013-1484-2

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  • DOI: https://doi.org/10.1007/s00726-013-1484-2

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