The heparin binding growth factors midkine and pleiotrophin regulate the antinociceptive effects of morphine through α(2)-adrenergic independent mechanisms.

Genetic deletion of pleiotrophin (PTN) impairs spinal nociceptive transmission suggesting that this heparin binding growth factor could play roles in acute pain processing. Despite the high functional redundancy between PTN and midkine (MK), the only other member of this family of growth factors, we now demonstrate that genetic inactivation of MK does not alter acute nociceptive transmission since pain responses of female MK genetically deficient (MK-/-) and wild type (WT+/+) mice were found to be similar in the hot-plate and tail-immersion tests. It has also been shown that morphine administration significantly regulates MK levels within the brain, suggesting that MK could play a role in morphine-induced antinociceptive effects. To test this hypothesis, we have now studied morphine-induced antinociceptive effects in female MK-/- and WT+/+ mice. We did not find differences among genotypes using different doses of morphine (2.5, 5 and 10 mg/kg) in the hot-plate test. In contrast, we found that morphine significantly delayed pain responses in MK-/- mice compared to WT+/+ mice in the tail-immersion test. In confirmation of previous results from our group, we also found significantly enhanced morphine-induced antinociceptive effects in PTN-/- mice in the tail-immersion test. In addition, we now demonstrate that enhanced morphine analgesic effects in PTN-/- and MK-/- mice are not caused by a different contribution of descending noradrenergic inhibitory pathways since the α(2)-adrenergic antagonist yohimbine failed to alter morphine-induced analgesia in all genotypes. The data demonstrate that MK is an endogenous modulator of morphine antinociceptive effects, identify significant differences between PTN and MK in the control of pain processing at the spinal level, and support the hypothesis that inhibitors of the PTN/MK signaling pathway could potentiate opioid analgesia which may be relevant in opioid-refractory pain cases.