Chronic exposure of neonatal rat adrenomedullary chromaffin cells to opioids in vitro blunts both hypoxia and hypercapnia chemosensitivity
Authors: Salman Shaima , Buttigieg Josef , Zhang Min , Nurse Colin A. 
Published: November 2012

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 agonists in 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 KATP channels, 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 O2 and CO2 chemosensitivity; 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 agonists in utero and in vitro suppressed 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 KATP current density and the KATP channel subunit Kir6.2, and was reversed by the KATP channel blocker, glibenclamide. By contrast, suppression of hypercapnia sensitivity was associated with down‐regulation of two key mediators of CO2 sensing, 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.