Neuroscience
-
Although micro opioid receptor (MOR) agonists are used for treatment of most types of pain, a recent study has suggested that the sensitivity of bone cancer pain to systemic morphine was lower than that of inflammatory pain. However, the reasons for this have remained unclear. In this study, MOR expression and the analgesic effects of morphine in a bone cancer model were compared with those in an inflammatory pain model. ⋯ In sarcoma-implanted mice, the percentage of MOR-positive DRG neuronal profiles was lower than that in control mice (30.3% vs. 45.2%). In particular, MOR expression was reduced among calcitonin gene-related peptide- and transient receptor potential vanilloid subfamily 1-positive DRG neuronal profiles, which are considered to be involved in the generation of bone cancer pain (from 61.5% to 41.5% and from 72.1% to 48.4%, respectively). These results suggest that down-regulation of MOR in the distinct populations of DRG neurons contributes to the fact that higher doses of morphine are needed to produce analgesia in bone cancer as compared with those used in non-malignant inflammatory situations.
-
Cocaine effectively inhibits dopamine (DA) uptake and this action appears to be the primary cause for increased DA transmission following systemic cocaine administration. Although this action had been reliably demonstrated in vivo with cocaine at high doses, data on the extent and the time-course of DA uptake inhibition induced by i.v. cocaine at low, reinforcing doses remain controversial. To clarify this issue, we examined how cocaine affects striatal neuronal responses to repeated iontophoretic DA applications in urethane-anesthetized rats. ⋯ Both regimens of cocaine treatment did not result in evident changes in either onset or offset of the DA-induced inhibitions. Our data confirm that cocaine at low, reinforcing doses inhibits DA uptake, resulting in potentiation of DA-induced neuronal inhibitions, but they suggest that this effect is relatively weak and delayed from the time of i.v. injection. These slow and prolonged effects of i.v. cocaine on DA-induced neuronal responses are consistent with previous binding and our electrochemical evaluations of DA uptake, presumably reflecting the total time necessary for i.v.-delivered cocaine to reach brain microvessels, cross the blood-brain barrier, passively diffuse within brain tissue, interact with the DA transporters, and finally inhibit DA uptake.
-
5-HT(1A) autoreceptors regulate the firing of 5-HT neurons and their release of 5-HT. In previous immuno-electron microscopic studies, we have demonstrated an internalization of 5-HT(1A) autoreceptors in the nucleus raphe dorsalis (NRD) of rats, after the acute administration of a single dose of the specific agonist 8-hydroxy-2-(di-n-propylamine)tetralin (8-OH-DPAT) or of the selective 5-HT reuptake inhibitor, fluoxetine. Twenty-four hours after either treatment, the receptors were back in normal density on the plasma membrane of NRD neurons. ⋯ Interestingly, several laboratories have reported an uncoupling of 5-HT(1A) autoreceptors from their G protein in the NRD of rats chronically treated with fluoxetine. Therefore, the best explanation for our results is that, after repeated internalization and retargeting, functional 5-HT(1A) autoreceptors are replaced by receptors uncoupled from their G protein on the plasma membrane of NRD 5-HT neurons. Thus, the regulatory function of these autoreceptors may depend on a dynamic balance among their production, activation, internalization and recycling to the plasma membrane in inactivated (desensitized) form.
-
Plethodontid salamanders display intricate courtship behaviors. Proteinaceous courtship pheromones were recently discovered in the submandibular (mental) gland of the male Plethodon shermani, the red-legged salamander. Behavioral studies showed that these male pheromones are delivered by direct contact to the female snout and modulate her receptivity during courtship. ⋯ Unlike other known vertebrate reproductive pheromones, courtship pheromones in P. shermani were effective only at a high concentration. This could result from the particular mode of pheromone transfer in that species, which involves sustained direct contact between male and female. It is concluded that salamander courtship pheromones exert their influence on behavior through the vomeronasal pathway and its direct projections to the preoptic and hypothalamic regions.
-
mu-Opioid agonists frequently activate output neurons in the brain via disinhibition, that is, by inhibiting "secondary cells," which results in disinhibition of "primary cells," considered to be output neurons. Secondary cells are generally presumed to be inhibitory interneurons that serve only to regulate the activity of the output neurons. However, studies of the opioid-sensitive neurons in the rostral ventromedial medulla, a region with a well-documented role in nociceptive modulation, indicate that the opioid-inhibited neurons in this region (termed "on-cells" when recorded in vivo) have a distinct functional role that parallels and opposes the output of the subset of RVM neurons that are activated following opioid administration, the "off-cells." The aim of the present study was to analyze the relative timing of on- and off-cell reflex-related firing in the rostral ventromedial medulla to help determine whether on-cells are likely to function as inhibitory interneurons in this region. ⋯ Contrary to what would be expected if on-cells were inhibitory interneurons, off-cells typically ceased firing before on-cells began reflex-related firing, with a mean 481 (+/-69) ms lag between the final off-cell spike and the first on-cell spike. This suggests that on-cells do not mediate the off-cell pause, and points instead to presynaptic mechanisms in opioid-mediated disinhibition of medullary output neurons. These data also support an independent role for on-cells in pain modulation.