The ability of delta opioid receptors in the spinal cord to mediate antinoci-ception is well established but the ability of delta opioid receptors to mediate antinociception at the supraspinal level continues to be a subject of controversy. A preponderance of evidence seems to support supraspinal anti-nociception mediated by delta opioid receptors [27,42], however, the dispute still continues. Pharmacological evidence in favor of delta opioid-mediated antinociception in the brain can be summarized as: 1) the ability of highly selective delta opioid receptor agonists [35,50] to produce antinociceptive responses to chemical and thermal nociceptive stimuli in mice when give ICV; 2) the ability of selective delta opioid receptor antagonists to block these agonist effects; 3) the insensitivity of delta opioid receptor agonist-induced suparaspinal antinociception to mu opioid receptor antagonists; and 4) a lack of cross-tolerance between selective delta and mu opioid receptor agonists to produced supraspinal antinociception. On the contrary, a virtually absolute requirement from mu , but not delta, opioid receptor expression to allow expression of delta opioid receptor agonist-induced supraspinal antinociception has been proposed [59,73,154,155].
Mice lacking DOR-1 are markedly less sensitive to spinal antinocicep-tion induced by both DPDPE and [D-Ala2]deltorphin II given ITH , indicating a major contribution of DOR-1 to spinal antinociception. However, both DPDPE and [D-Ala2]deltorphin II retain their antinociceptive activity, with no reduction in potency, following ICV administration in DOR-1 knockout mice . The retained antinociception induced by those agonists is only partially antagonized by NTI. Under these conditions, the nonpeptide delta opioid receptor agonist BW373U69 exhibits enhanced activity in DOR-1 mutant mice . Such findings are unexpected in light of extensive pharmacological literature supporting antinociception mediated by the delta opioid receptor in the brain. In contrast, supraspinal antinociception induced by ICV administration of delta opioid receptor agonists is dramatically reduced in MOR-1 gene knockout mice in a gene dose-dependent fashion . These findings suggest that the mu opioid receptor is necessary for delta opioid receptor agonist-induced supraspinal antinociception.
Although each type of opioid receptor can transduce its effects independently, evidence has been accumulating for the existence of cellular and/or molecular interactions between them. Thus, the cross-talk between mu and delta opioid receptors has been proposed on the basis of pharmacological studies demonstrating both competitive and noncompetitive changes in the binding of delta-selective ones [155,156]. Conversely, administration of delta opioid receptor antagonists, or of antisense oligodeoxynucleotide directed against DOR-1, is shown to reduce the development of tolerance to the antinociceptive effects of morphine [157-159]. Accordingly, DOR-1 knockout mice maintain mu opioid receptor-mediated antinociception but show a decrease in the development of tolerance to morphine . In contrast, prolonged stimulation of neurons with morphine markedly increases recruitment of intracellular delta opioid receptors to the cell surface without any changes in protein levels of delta opioid receptors . Recent evidence using transfected cell systems demonstrates direct molecular interactions between different members of the opioid receptor family, with reports if heterodi-merization of the delta opioid receptor with either the mu [161,162] or kappa-opioid receptor . These findings indicate that heterodimerization of delta and mu or kappa opioid receptors could account for the cross-modulation among opioid receptors. Furthermore, delta opioid receptors are considered to form heteromeric complexes with h2-adrenergic receptor  and V2 vasopressin receptors . It is therefore likely that the delta opioid receptor directly interacts with other receptors including mu opioid receptor involved in the modulation of supraspinal antinociception induced by delta opioid receptor agonists in the brain.
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