Strain Differences in the Delta Opioid Receptor Agonist Properties of the Multifunctional Opioid Glycopeptide MMP2200

Abstract

Mu-opioid receptor (MOR) agonists, such as morphine, are clinically effective analgesics but present a host of serious side effects including constipation, respiratory depression, tolerance, and dependence. Therefore, there is a clinical need for safer and more effective analgesics for the treatment of chronic pain. Previous literature has provided evidence that coactivation of mu and delta opioid receptors (MOR, DOR, respectively) produce antinociceptive effects with reduced side effects. MMP2200, or lactomorphin, is a glycosylated peptide based on the structure of enkephalin and has been demonstrated to have equal affinity for DOR and MOR in vitro. A previously published study characterized the MOR effects in vivo. However, little is known about the DOR-mediated effects. Therefore, the goal of this study was to assess DOR-mediated behaviors in male and female C57BL/6N and ICR mice. We hypothesized that MMP2200 would produce DOR-mediated convulsions and antidepressant-like effects in the mouse forced swim test in both mouse strains. Male and female C57BL6/N and ICR mice (Envigo) were individually and continuously observed for 30-60 min in clear observation cages, and all behavioral changes were noted. Latency to convulse and duration of convulsion and catalepsy were recorded, and a modified Racine score was used to assess severity of convulsions. Antidepressant-like effects were measured in the forced swim test (6 min, 25°C, 3-4 L tap water) in C57BL6/N mice. MMP2200 produced dose-dependent, DOR-mediated convulsions in both male and female C57BL6/N mice but did not produce convulsions in ICR mice up to the largest doses tested (100 mg/kg). Further, MMP2200 did not enhance the convulsive effects of pentylenetetrazol (PTZ) in ICR mice, unlike other DOR agonists such as SNC80. MMP2200 did not alter immobility in the mouse forced swim test, suggesting that it does not have antidepressant-like effects in C57BL6/N mice. Additionally, no antidepressant-like effect was revealed by blocking the MOR with the irreversible antagonist bFNA (32 mg/kg, 48 h). In summary, MMP2200 produced strain-dependent convulsive effects but no antidepressant-like effects. This unique profile suggests that DOR-mediated behavioral effects of multifunctional opioid ligands may be different than those produced by selective DOR agonists, and future studies will examine the role that the MOR agonist properties may play in mediating these effects. Finally, these results highlight the importance of strain differences when assessing DOR agonist activity in vivo.