Kappa opioid receptors in rat spinal cord: sex-linked distribution differences

Activation of kappa opioid receptors (KORs) in the spinal cord can diminish nociception. Humans and rodents show sex differences in the analgesia produced by KOR agonists, and female rats show fluctuations in KOR density and sensitivity across the estrous cycle. However, it is unclear whether there are sex differences in the amount and/or distribution of spinal KORs. In the present study, immunocytochemically labeled KORs were examined in laminae I and II of the lumbosacral spinal dorsal horn of male and normally cycling female Sprague-Dawley rats. The basic pattern of KOR labeling was determined in both sexes using qualitative electron microscopy (EM), and sex-linked differences in the density and subcellular distribution of KOR immunoreactivity were determined with quantitative EM and light microscopy. KOR labeling was visualized with immunoperoxidase for optimally sensitive detection, or with immunogold for precise subcellular localization. By EM, the general pattern of KOR immunoreactivity was similar in males and females. KOR immunoreactivity was common in dendrites, axons, and axon terminals, and was in a few glia and neuronal somata. Most KOR-immunoreactive (-ir) axons were fine-diameter and unmyelinated. Most KOR-ir terminals were small or medium-sized, and a minority formed asymmetric or symmetric synapses with unlabeled dendrites. KOR immunoreactivity was associated both with the plasma membrane and with cytoplasmic organelles, notably including dense core vesicles in terminals. Light microscopic densitometry revealed that KOR immunoreactivity was significantly denser in estrus and proestrus females than in males. By EM, the distribution of KOR-immunogold labeling within axon terminals differed, with a greater proportion of cytoplasmic KOR labeling in estrus females compared with males. In contrast, the abundance and types of KOR-immunoperoxidase-labeled profiles did not show sex-linked differences. We conclude that in both sexes, KORs are positioned to influence both pre- and postsynaptic neurotransmission and are present in morphologically heterogeneous neuron populations. These findings are consistent with complex consequences of KOR activation in the spinal cord. In addition, the presence of increased KOR density and proportionally elevated intracellular KORs in proestrus/estrus females suggests a basis for sex-linked differences in KOR-mediated antinociception.