Cardiorespiratory action of opioid/tachykinin agonist peptide hybrid in anaesthetized rats: Transduction pathways

AWL3106 composed of opioid (dermorphin) and tachykinin (substance P7–11) pharmacophores is a new compound with high analgesic potency and markedly reduced ability to induce tolerance and dependence. The present study aimed to determine the respiratory and cardiovascular responses evoked by this peptide in urethane-chloralose anaesthetized, spontaneously breathing rats in the presence or absence of vagal connection. Intravenous injection of AWL3106 at a dose of 0.3μmol/kg in intact rats resulted in apnoea lasting 5.1 ± 0.7s. Breathing that followed was of diminished frequency (F) and augmented tidal volume (VT) with no significant impact on minute ventilation. AWL3106-challenge induced biphasic fall in arterial blood pressure with no effect on heart rate. Midcervical and supranodosal sectioning the vagal nerves prevented the occurrence of the apnoea and abrogated the post-AWL3106 reduction in F but failed to eliminate the increase in VT. Hypotensive response appeared to be less profound following supranodose vagotomy. NaloxoneHCl abolished solely the occurrence of apnoea. However additional blockade of tachykinin NK1 receptors with SR140333 was required to abolish VT increase, deceleration of breathing and to markedly suppress AWL3106-induced hypotension. The present study shows that extravagally controlled stimulation of VT maintains fairly regular ventilation by levelling the bradypnoeic effects. Although the peptide showed no cardiac effects, hypotension occurring beyond the vagal loop may limit future therapeutic benefits of this chimeric compound.