Chronic exposure of neonatal rat adrenomedullary chromaffin cells to opioids<i>in vitro</i>blunts both hypoxia and hypercapnia chemosensitivity
Bibliographic record
Abstract
Key points Low O2(hypoxia) and high CO2(hypercapnia) elicit a critical, non‐neurogenic catecholamine surge from neonatal rat adrenomedullary chromaffin cells (AMCs), but these chemosensing mechanisms are suppressed postnatally following splanchnic innervation. We tested the possibility that opioids released from the splanchnic nerve during innervation contribute to the suppression of chemosensitivity using a culture model of dissociated neonatal rat AMCs exposed to opioid agonistsin vitro. Exposure of neonatal AMCs to μ‐ and/or δ‐opioid agonists for ∼1 week led to a naloxone‐sensitive blunting of both hypoxia and hypercapnia sensitivity. The loss of hypoxia sensitivity was attributable to the increased expression of glibenclamide‐sensitive KATPchannels, which open during acute hypoxia favouring membrane hyperpolarization; by contrast, the loss of hypercapnic sensitivity was associated with the down‐regulation of carbonic anhydrase I and II. Thus, stimulation of postsynaptic opioid receptors on chromaffin cells following splanchnic innervation may normally contribute to the postnatal suppression of direct O2and CO2chemosensitivity; also, prenatal exposure to opioid drugs could lead to impaired chromaffin cell responses to asphyxial stimuli in the neonate. Abstract At birth, rat adrenomedullary chromaffin cells (AMCs) respond directly to asphyxial stressors such as hypoxia and hypercapnia by triggering catecholamine secretion, which is critical for proper transition to extrauterine life. These non‐neurogenic responses are suppressed postnatally in parallel with the development of splanchnic innervation, and reappear following denervation of the adult adrenal gland. To test whether neural factors released from the splanchnic nerve may regulate AMC chemosensitivity, we previously showed that nicotinic agonistsin uteroandin vitrosuppressed hypoxia, but not hypercapnia, sensitivity. Here, we considered the potential role of opiate peptides which are also released from the splanchnic nerve and act via postsynaptic μ‐, δ‐ and κ‐opioid receptors. Treatment of neonatal rat AMC cultures for ∼1 week with μ‐ and/or δ‐ (but not κ) opioid agonists (2 μm) led to a marked suppression of both hypoxia and hypercapnia sensitivity, as measured by K+current inhibition and membrane depolarization; co‐incubation with naloxone prevented the effects of combined opioids. The suppression of hypoxia sensitivity was attributable to upregulation of KATPcurrent density and the KATPchannel subunit Kir6.2, and was reversed by the KATPchannel blocker, glibenclamide. By contrast, suppression of hypercapnia sensitivity was associated with down‐regulation of two key mediators of CO2sensing, i.e. carbonic anhydrase I and II. Collectively, these studies point to a novel role for opioid receptor signalling in the developmental regulation of chromaffin cell chemosensitivity, and suggest that prenatal exposure to opioid drugs could lead to impaired arousal responses in the neonate.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".