Dopamine D4 receptor activation preserves morphine analgesia and attenuates tolerance by enforcing inhibitory spinal tone in rats

Abstract The clinical efficacy of opioid-based therapies is severely limited by the emergence of maladaptive neuroplasticity which drives both analgesic tolerance and paradoxical pain sensitization. Although these processes involve spinal nociceptive circuits, the endogenous modulatory systems capable of selectively restraining maladaptive plasticity without compromising opioid analgesia, remain incompletely characterized. The dopamine D4 receptor (D4R) has been previously shown to constrain morphine-induced neuroadaptations within supraspinal circuits that underlie addiction, positioning it as a compelling candidate to regulate opioid-induced plasticity at the spinal level. Here, we investigated whether D4R activation modulates spinal mechanisms underlying morphine tolerance and hyperalgesia. Using integrated behavioral, molecular, and neuroanatomical approaches in rats, we show that D4R activation preserves morphine antinociception while attenuating tolerance and preventing hyperalgesia. This effect is mediated by selective reshaping of dorsal horn circuitry, including modulation of non-peptidergic C fibers afferents, enhancement of catecholaminergic tone, and a shift of the excitatory-inhibitory balance toward inhibition. At the cellular level, D4R activation attenuates CREB-dependent signaling and reduces neurokinin-1 (NK1) receptor availability in lamina I projection neurons, which constitute the main spinal output to supraspinal nociceptive centers. Together, these findings identify D4R as a state-dependent modulator of spinal nociceptive circuitry that selectively contains opioid-induced maladaptive plasticity while sparing analgesic signaling. These results extend the regulatory role of D4R from supraspinal addiction-related circuits to spinal pain pathways, highlighting its potential as a therapeutic target to improve the long-term safety of opioid analgesia. Perspective D4R emerges as a key regulator linking supraspinal addiction-related circuits and spinal nociceptive pathways. By restraining maladaptive plasticity while preserving opioid analgesia, D4R offers a state-dependent mechanism to prevent tolerance and hyperalgesia. Targeting D4R could thus provide a novel strategy to enhance the long-term safety and efficacy of opioid therapies.