The design of novel drugs for pain relief with improved analgesic properties and diminished side effect induction profile still remains a challenging pursuit. Tolerance is one of the most burdensome phenomena that may hamper ongoing opioid therapy, especially in chronic pain patients. Therefore, a promising strategy of hybridizing two pharmacophores that target distinct binding sites involved in pain modulation and transmission was established. Previous studies have led to the development of opioid agonist/NK1 agonist hybrids that produce sufficient analgesia and also suppress opioid-induced tolerance development. In our present investigation we assessed the antinociceptive potency of a new AA3052 chimera comprised of a potent MOR selective dermorphin derivative (DALDA) and an NK1 agonist, a stabilized substance P analogue. We have shown that AA3052 significantly prolonged responses to both mechanical and noxious thermal stimuli in rats after intracerebroventricular administration. Additionally, AA3052 did not trigger the development of tolerance in a 6-day daily injection paradigm nor did it produce any sedative effects, as assessed in the rotarod performance test. However, the antinociceptive effect of AA3052 was independent of opioid receptor stimulation by the DALDA pharmacophore as shown in the agonist-stimulated G-protein assay. Altogether the current results confirm the antinociceptive effectiveness of a novel opioid/SP hybrid agonist, AA3052, and more importantly its ability to inhibit the development of tolerance.
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