When agonists to α2adrenergic receptor (AR) and δ opioid receptor (DOR) are co-administered, they act synergistically to inhibit nociceptive elicited behavior. Some previous studies of synergism have used the DOR-selective agonist [D-Pen2,D-Pen5]-enkehphalin (DPDPE), however, DPDPE has been shown to be less potent in μ opioid receptor-knockout (MOR-KO) mice. It is possible, therefore, that MOR contributes to the synergism of DPDPE with the α2AR agonists. We compared the interactions of spinally administered DPDPE with an α2AR-adrenergic agonist in MOR-KO and MOR-wildtype (WT) mice. In these mice, morphine is ineffective and the potency of spinally administered DOR agonists, deltorphin II (DELT II) and DPDPE decreased 16- and 250-fold, respectively. Antagonism studies using the MOR-selective antagonist, D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Phe-Thr-NH2 (CTOP) and the DOR-selective antagonist, naltrindole HCl (naltrindole) demonstrated that while DOR mediates DPDPE-induced antinociception in MOR-KO, both MOR and DOR participate in DPDPE antinociception in WT mice, suggesting that DPDPE is less selective for DOR than previously observed in binding studies when given in vivo. The potency of the α2AR agonist UK14,304 was equivalent in WT and MOR-KO, demonstrating that the loss of opioid-mediated antinociception in the MOR-KO was not due to generalized impairment of antinociceptive processing. Interestingly, isobolographic analysis showed that, despite substantial loss of DPDPE potency in MOR-KO, DPDPE-UK14,304 synergism is fully retained. Collectively, these experiments demonstrate that although MOR participates in DELT II- and DPDPE-mediated spinal antinociception, DOR independently participates in synergistic antinociception with α2AR. Resolution of the roles of the opioid receptor subtypes in opioid agonist-induced effects may require comparison of the effects of multiple selective agonists in knockout animals.
Bibliographical noteFunding Information:
We extend our great appreciation to Drs George L. Wilcox and Ping-Yee Law, Tinna M. Laughlin, Rachid E.L. Kouhen and Smita Kshirsagar for useful conversations; to Dr Michael H. Ossipov for computational assistance with isobolographic analysis; to Mr Kelley F. Kitto, Ms H. Oanh Nguyen, Mr Tyler Crockett and Ms Lori Kaminski for excellent technical assistance. Supported by DA-00546, DA-01583 and by the A.F. Stark Fund of the Minnesota Medical Foundation (HHL); NCCAM training grant P50AT00009-02 and DA-00509-01A1 supported C.A.F.
- Deltorphin II
- μ opioid receptor-knockout mice