Isoflurane depression of spinal nociceptive processing and minimum alveolar anesthetic concentration are not attenuated in mice expressing isoflurane resistant γ-aminobutyric acid type-A receptors

Abstract

Anesthetics produce immobility and depress spinal nociceptive processing, but the exact sites and mechanisms of anesthetic action are unknown. The gamma-aminobutyric acid type-A (GABA A ) receptor is thought to be important to anesthetic action. We studied knockin mice that had mutations in the alpha1 subunit of the GABA A receptor that imparts resistance to isoflurane in in vitro systems. We determined the isoflurane minimum alveolar concentration (MAC) that produces immobility in 50% of subjects and responses of lumbar neurons (single-unit recordings) to noxious stimulation (5 s pinch) of the hindpaw. Isoflurane MAC did not differ between wildtype (1.1 ± 0.1%) and knock-in (1.1 ± 0.1%) mice. Isoflurane depressed neuronal responses to noxious stimulation (60 sec period during and after pinch) similarly in both wild-type and knockin mice (555 ± 133 and 636 ±106 impulses/min, respectively, at 0.8 MAC and 374 ± 81 and 409 ±85 impulses/min at 1.2 MAC). We conclude that isoflurane enhancement of alpha1 -containing GABA A receptors is not required to produce immobility or depress spinal nociceptive processing. KeywordsSpinal cord; GABA receptor; isoflurane; immobility; anesthesia Anesthetics are widely used but we still do not fully understand how these powerful and potentially unsafe drugs produce general anesthesia, which includes amnesia, unconsciousness and immobility. Analgesia and control of autonomic responses to noxious stimuli are also desirable components of general anesthesia [1]. Immobility is determined

Gamma-Aminobutyric Acid Type A Receptor Alpha 4 Subunit Knockout Mice Are Resistant to the Amnestic Effect of Isoflurane

“…These results are consistent with previous pharmacologic studies that have demonstrated that GABA A -Rs in the spinal cord are not key mediators of anesthetic-induced immobility 29,30…”

Rat Dorsal Horn Nociceptive-Specific Neurons Are More Sensitive Than Wide Dynamic Range Neurons to Depression by Immobilizing Doses of Volatile Anesthetics: An Effect Partially Reversed by the Opioid Receptor Antagonist Naloxone

“…Evoked responses of dorsal horn neurons to noxious stimuli have reportedly been depressed by periMAC dose increases of halothane and isoflurane 8–11,19. However, further studies failed to confirm isoflurane-induced depression of dorsal horn neurons and suggest periMAC increases of isoflurane dose may facilitate neuronal response to noxious stimulation 10,11.…”

Some heightened sensitivity

“…On the one hand, mice expressing an isoflurane-resistant knock-in α1 GABA A receptor subunit did not change either MAC or the suppression of neuronal responses to noxious stimulation. 10 Yet sensitivity to other GABAergic sedatives, including methohexital 11 and midazolam, 12 also increases with ageing. Perhaps ageing-related changes in GABA A receptor subunit expression or other, compensatory modifications that occur with ageing could explain the increased sensitivity to anaesthetics in older animals.…”