Ontogeny and distribution of opioid receptors in the rat brainstem

Abstract

The distribution and postnatal ontogeny of opioid receptors have been investigated using in vitro quantitative receptor autoradiography. Rats were studied at postnatal day 1 (P1), P5, P10, P21 and P120 (adult). Opioid receptor sites for (d-Ala²,N-MePhe⁴,Gly-ol⁵)-enkephalin (DAMGO) binding were labelled with 4 nM of³H-DAMGO; (d-Ala²,d-Leu⁵)-enkephalin (DADLE) binding sites were labelled with 4 nM of³H-DADLE in the presence of 1 μM unlabelled μ-agonist (N-MePhe³,d-Pro⁴)-morphiceptin (PL017). We found that both binding sites have strikingly different distributional patterns. [³H]DADLE binding sites were rather homogeneous, whereas the distribution of [³H]DAMGO binding was very heterogeneous with the highest density in the nucleus of the solitary tract (NTS), ambiguus nucleus, dorsal motor nucleus of the vagus and the parabrachial areas. [³H]DAMGO binding density was 2- to 40-fold higher than [³H]DADLE binding sites in most brainstem nuclei. [³H]DAMGO binding sites appeared in most brainstem nuclei at birth, with a high density in cardiorespiratory-related nuclei, whereas [³H]DADLE binding sites were too scarce to be quantitated at P1. Both binding sites increased with age, but the developing patterns depended on the nucleus and the type of binding site. In most areas, the densities of both binding sites reached a maximum between P10 and P21 and then decreased to an adult level, but in some nuclei (e.g. the caudal part of the NTS and dorsal raphe nucleus), [³H]DAMGO binding sites kept increasing until adulthood. In contrast with the brainstem, cortical areas had a lower binding density in the newborn and reached peak levels later than brainstem regions (post P21). We conclude that (1) since [³H]DAMGO binding sites mainly reflect μ-receptors and [³H]DADLE binding sites δ-receptors (in the presence of PL017), the brainstem is essentially a μ-receptor region though δ-receptors are present; (2) both opioid receptors are present at birth but δ-receptors are very scarce in the newborn; (3) both receptors increase with age, but the time course depended on various nuclei and receptor types; (4) cardiorespiratory-related nuclei have high density of μ-receptors at all ages; and (5) opioid receptors develop earlier in the brainstem than in the cortex.