Neurotensin NTS1 receptors mediate the cardio-respiratory effects of [Ile 9]PK20, a novel chimeric peptide

• Autorzy: Kaczynska K. , Szereda-Przestaszewska M. , Kleczkowska P. , Lipkowski A. W.
• Języki publikacji: EN

Abstrakty

EN

Opioids with their large potency in pain relieve have certain undesirable effects like tolerance, dependence and respiratory depression. This is the reason for permanent efforts to create new analgesic compounds devoid of the adverse side effects. PK20 is a novel hybrid of opioidneurotensin peptides synthetized from the C-terminal hexapeptide of neurotensin and endomorphine-2 pharmacophore. This chimeric compound shows clear central and peripheral antinociceptive activity in experimental animals, however nothing is known about the influence of PK20 on respiratory and cardiovascular parameters. The present study was designed to determine the cardiorespiratory effects exerted by an intravenous injection of [Ile9]PK20, analog of PK20 with substitution of tert-leucine by isoleucine9. We also attempted to evaluate whether the effects of the hybrid are mediated by the peripheral neural pathway like vagus nerve. Finally, the contribution of NTS1 neurotensin and opioid receptors in the [Ile9]PK20 cardiorespiratory pattern was tested. Anaesthetized, spontaneously breathing rats were used. Tidal volume was measured at tracheostomy. The timing components of the breathing pattern, arterial blood pressure and heart rate were recorded. Intravenous injection of [Ile9]PK20 at a dose of 100 μg/kg in the intact rats provoked an increase in tidal volume preceded by a prompt shortlived decrease. Immediately after the end of injection brief acceleration of the respiratory rhythm, was ensued by the slowing down of breathing. Changes in respiration were concomitant with a bi-phasic response of the blood pressure: immediate increase was followed by prolonged hypotension. Bilateral midcervical vagotomy eliminated both: tidal volume and respiratory rate responses. Blockade of NTS1 receptors with an intravenous dose of 500 μg/kg of SR 142948, significantly lessened post-[Ile9]PK20 cardiorespiratory effects. Naloxone hydrochloride – antagonist of opioid receptors – failed to block [Ile9]PK20-evoked responses. This study depicts that [Ile9]PK20 acting through neurotensin NTS1 receptors augments the tidal component of the breathing pattern through the vagal pathway. This latter mediates also the respiratory timing response to the drug. Blood pressure effects evoked by an intravenous injection of [Ile9]PK20 occur besides the vagal pathway and might result from activation of the central and peripheral vascular NTS1 receptors. In summary the respiratory effects appeared not to be profound. However, considerable and extended hypotension evoked by [Ile9]PK20 sets the main disadvantage of an analgesic compound.

Słowa kluczowe

EN

neurotensin 1 receptor; cardio-respiratory effect; opioid; respiratory depression; PK20 peptide; opioid-neurotensin hybrid peptide; new peptide; chimeric peptide; endomorphine-2 pharmacophore

• Wydawca: -
• Czasopismo: Acta Neurobiologiae Experimentalis
• Rocznik: 2013
• Tom: 73
• Numer: 1
• Opis fizyczny: p.176-177

Twórcy

autor

Kaczynska K.

• Laboratory of Respiratory Reflexes, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland

autor

Szereda-Przestaszewska M.

• Laboratory of Respiratory Reflexes, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland

autor

Kleczkowska P.

• Department of Neuropeptides, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland

autor

Lipkowski A. W.

• Department of Neuropeptides, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland