Behavioral effects of combined morphine and MK-801 administration to the locus coeruleus of a rat neuropathic pain model

The persistent activation of N-methyl-d-aspartate acid receptors (NMDARs) seems to be responsible for a series of changes in neurons associated with neuropathic pain, including the failure of opioids that act through mu-opioid receptors (MORs) to provide efficacious pain relief. As the noradrenergic locus coeruleus (LC) forms part of the endogenous analgesic system, we explored how intra-LC administration of morphine, a MORs agonist, alone or in combination with MK-801, a NMDARs antagonist, affects the sensorial and affective dimension of pain in a rat model of neuropathic pain; chronic constriction injury (CCI). Intra-LC microinjection of morphine induced analgesia in CCI rats, as evident in the von Frey and cold plate test 7 and 30 days after surgery, although it was not able to reverse pain-related aversion when evaluated using the place escape/avoidance test. However, the thermal anti-nociception produced by morphine was enhanced when it was administered to the LC of CCI animals in combination with MK-801, without altering its effects on the mechanical thresholds. Furthermore, pain-related aversion was reduced by co-administration of these agents, yet only in the short-term CCI (7 day) rats. Overall the data indicate that administration of morphine to the LC produces analgesia in nerve injured animals and that this effect is potentiated in specific pain modalities by the co-administration of MK-801. While a combination of morphine and MK-801 could reduce pain-related aversion in short-term neuropathic animals, it was ineffective in the long-term, suggesting that its sensorial effects and its influence on the affective component of pain are regulated by different mechanisms.