A dose‐response analysis of the beneficial effects of the ACTH‐(4–9) analogue, Org 2766, on behavioural recovery following unilateral labyrinthectomy in guinea‐pig

Abstract

1. After removal of the peripheral vestibular receptors in one inner ear (unilateral labyrinthectomy, UL), oculo-motor and postural symptoms occur but disappear over time in a process of recovery known as vestibular compensation. 2. ACTH-(4-10), a fragment of the adrenocorticotrophic hormone (ACTH) molecule, which is devoid of corticotrophic activity, has been shown to enhance vestibular compensation. The present study investigated the effect of the ACTH-(4-9) analogue, Org 2766, on vestibular compensation in guinea-pig. Org 2766 is reported to be more potent behaviourally than ACTH-(4-10). 3. After UL, Org 2766 was delivered via an osmotic minipump implanted s.c. to 30 animals randomly assigned to one of five conditions: 1, 5, 10, 20 or 40 nmol kg-1 Org 2766, every 4 h for 52 h post-UL. Although infusion was continuous, in the present study the doses are expressed as nmol per 4 h in order to compare the results to a previous study in which animals received a discrete dose of ACTH-(4-10) at the end of each 4 h period. All animals were compared to saline controls (n = 6). 4. Three symptoms of UL, spontaneous ocular nystagmus, roll head tilt and yaw head tilt, were measured every 4 h for 52 h, beginning at 10 h post-UL. 5. Rates of infusion of 1, 5 and 10 nmol kg-1 accelerated spontaneous nystagmus compensation; 20 nmol kg-1 produced a significant decrease in the frequency of spontaneous nystagmus, as well as accelerating its compensation; 40 nmol kg-1 had no significant effect on spontaneous nystagmus compensation. 6. In comparison to the effects of Org 2766 on spontaneous nystagmus compensation, Org 2766 had little effect on the compensation of the postural symptoms, yaw head tilt and roll head tilt. Only 5 and 40 nmol kg-1 produced a significant change in postural compensation, and this was a reduction in the rate of roll head tilt compensation.7. At the optimal infusion rate of 20 nmol kg-1 every 4 h, Org 2766 produced a similar effect on spontaneous nystagmus compensation to that of ACTH-(4-10). However, Org 2766 was effective in accelerating spontaneous nystagmus compensation at much smaller doses per 4 h period than ACTH-(4-10). Org 2766 did not have the same effect on. postural compensation as it had on the compensation of spontaneous nystagmus.