Direct evidence for systems-level modulation of initial drug (in)sensitivity in rats

Some argue that pharmacological effects trigger corrective regulatory responses of varying strength. If so, some commonly used in vivo measures of initial drug sensitivity are difficult to interpret because the measured effects represent a combination of underlying pharmacological effects and regulatory counter-responses with the relative contribution of each influenced by individual and dose-related factors.

The objective of this study was determine if core temperature (T (core)), a common measure in drug research, can mask the variability both in underlying pharmacological effects and physiological counter-responses during an initial administration of the hypothermia-promoting drug, nitrous oxide (N(2)O).

T (core) was measured synchronously with its determinants, heat production (HP) and heat loss (HL) during steady-state N(2)O administration. Drug-naive rats received a 90-min exposure to 0, 15, 30, 50, 60, or 75% N(2)O plus a paired control gas exposure (n > or = 8 per group). HP was measured via indirect calorimetry, HL via direct calorimetry, and T (core) via telemetry.

T (core) was unaltered by concentrations < or =50% N(2)O, but at 30 and 50% N(2)O, this stability masked significant increases of HL that were offset by increases of HP. On average, hypothermia accompanied 60 and 75% N(2)O inhalation owing to uncompensated increases of HL. However, some rats administered with these doses also exhibited T (core) stability via significant opposing changes of HL and HP.

A common in vivo measure of initial drug sensitivity can fail to disclose underlying pharmacological sensitivity owing to regulatory counter-responses. This concept has implications for understanding relationships between phenotypic variation in initial drug sensitivity and subsequent drug-taking phenotypes.