Morphine is one of the most effective analgesics used in the clinical management of pain. However, prolonged exposure to morphine results in a broad spectrum of adverse effects, including tolerance and addiction. Our prior findings indicate that the activation of the dopamine D4 receptor (D4R) prevents morphine addiction by modulating dopamine signalling in striatal regions involved in drug-habit formation and consolidation, without altering morphine-induced analgesia. Furthermore, it has been demonstrated that D4R in the terminals of primary nociceptors contributes to the anti-nociceptive effect of dopamine. In this study, we evaluate the impact of a combined treatment of morphine with a D4R agonist in the treatment of acute inflammatory pain, with a special emphasis on the development of analgesic tolerance. Methods: Sprague Dawley rats were administered morphine and/or PD168,077 (D4R agonist) over 8 days. On days 1 and 8, 15 minutes after drug administration, formalin was subcutaneously injected into the hind paw of the rats, and pain behaviour signals were subsequently evaluated. Immunohistochemistry was used to assed the expression of the transcription factors: cFos (related with pain response), P-CREB (linked to opioid tolerance) and Pax2 (GABAergic marker) in the laminae I and II of the dorsal horn. Results: D4R activation prevents morphine-induced tolerance, which correlate with a specific signature of transcription factor expression. Conclusion: the results open up the possibility of using a D4R agonist in combination with morphine as a novel strategy for treating pain. Supported by CTS-161 and UMA20-FEDERJA-122 (Junta de Andalucía, Spain).