Altered Hematopoiesis, Behavior, and Sexual Function in μ Opioid Receptor–deficient Mice

Abstract

The μ opioid receptor is thought to be the cellular target of opioid narcotics such as morphine and heroin, mediating their effects in both pain relief and euphoria. Its involvement is also implicated in a range of diverse biological processes. Using a mouse model in which the receptor gene was disrupted by targeted homologous recombination, we explored the involvement of this receptor in a number of physiological functions. Mice homozygous for the disrupted gene developed normally, but their motor function was altered. Drug-naive homozygotes displayed reduced locomotor activity, and morphine did not induce changes in locomotor activity observed in wild-type mice. Unexpectedly, lack of a functional receptor resulted in changes in both the host defense system and the reproductive system. We observed increased proliferation of granulocyte-macrophage, erythroid, and multipotential progenitor cells in both bone marrow and spleen, indicating a link between hematopoiesis and the opioid system, both of which are stress-responsive systems. Unexpected changes in sexual function in male homozygotes were also observed, as shown by reduced mating activity, a decrease in sperm count and motility, and smaller litter size. Taken together, these results suggest a novel role of the μ opioid receptor in hematopoiesis and reproductive physiology, in addition to its known involvement in pain relief.

μ Opiate Receptor Gene Dose Effects on Different Morphine Actions Evidence for Differential in vivo μ Receptor Reserve

“…Other work does support the idea that opioid receptors play only a modest role in morphine lethality. Differences in genetic background and/or testing conditions could also contribute to the modest differences between our locomotor data and that of Tian and coworkers (Tian et al 1997). These investigators reported reduced baseline spontaneous horizontal activity in knockout homozy- gous mice developed on a mixed genetic background.…”

“…Recent successes in developing transgenic knockout mice with receptor gene deletions (Matthes et al 1996;Sora et al 1997b;Tian et al 1997;Loh et al 1998) allow studies of morphine effects in animals that possess two, one, or no copies of the receptor gene. Heterozygous mice express half-normal levels of receptor expression in Scatchard analyses of [ 3 H][D-Ala 2 , N-MePhe 4 , Gly 5 -ol] enkephalin (DAMGO) binding to whole brain and in immunohistochemical analyses of receptor immunoreactivity in spinal cord and several other examined brain regions that included sections through striatum and locus coeruleus (Sora et al 1997b; I.S., R. Revay, and G.R.U., unpublished data).…”

Distinct molecular phenotype of malignant CD34+ hematopoietic stem and progenitor cells in chronic myelogenous leukemia

“…Incubation of CML mononuclear cells with DAMGO, a selective agonist of the opioid m1 receptor, or with the antagonist Naloxone had no effect on the clonogenic growth of lineage-committed progenitor cells. This is surprising since in a previous study an increased proliferation of granulocyte-macrophage, erythroid and multipotential progenitor cells in BM and spleen was found in opioid m1 receptor-deficient mice, suggesting a negative regulatory influence on normal hematopoiesis (Tian et al, 1997). Incubation of CML mononuclear cells with a specific antagonist of the adenosine A1 receptor resulted in a significant dosedependent inhibition of clonogenic growth of both, CFU-GM and BFU-E, suggesting a role in proliferation and differentiation of myelomonocytic as well as erythoid lineage-committed progenitor cells in CML.…”

Mediation of opioid analgesia by a truncated 6-transmembrane GPCR

“…7, 8). A number of μ-receptor KO mice eliminate morphine actions by targeting different regions of the gene (9,(12)(13)(14)(15), but individual mouse models may not completely eliminate all Oprm1 transcripts. Examples exist in which disruption of exon 1 does not impair the expression of the exon 11 variants (9) and in which elimination of exon 11 does not impact the expresThe generation of potent opioid analgesics that lack the side effects of traditional opioids may be possible by targeting truncated splice variants of the μ-opioid receptor.…”