Research articleAntagonism of orexin type-1 receptors (OX1Rs) attenuates naloxone-precipitated morphine withdrawal syndrome in rat dorsal hippocampus

- We examine the importance of hippocampus in morphine withdrawal syndrome.
- We evaluate role of orexinergic projections to hippocampus in morphine dependence.
- We can reduce the appearance of withdrawal symptoms by blocking hippocampal OX1R.

Herein the effect of hippocampal orexin type-1 receptors (OX1Rs) blockade on morphine withdrawal syndrome was studied. Animals were made dependent by subcutaneous (s.c.) administration of morphine sulfate (10 mg/kg) at an interval of 12 h for 9 consecutive days. Thereafter, on day 10, naloxone hydrochloride (1.5 mg/kg, i.p.) was injected and the somatic signs of withdrawal syndrome were monitored during a 25-min period. Two groups of animals received bilateral microinjection of either SB-334867, a selective OX1Rs antagonist, (0.5 μg/0.5 μl), or its vehicle into the dorsal hippocampus immediately before each morphine injection. Other groups of animals were made dependent at first and only received a single microinjection of SB-334867 or vehicle on day 10 before naloxone injection. The results showed that intra-hippocampal microinjection of SB-334867 before each morphine treatment, significantly decreased the signs of morphine withdrawal, including teeth chattering (dependent: 18.5 ± 2.3, SB treated: 5 ± 1, p < 0.001), diarrhea (dependent: 8.7 ± 0.6, SB treated: 4.1 ± 0.6, p < 0.001), ptosis (dependent: 33.8 ± 3.7, SB treated: 11.6 ± 1.1, p < 0.001), and chewing (dependent: 40 ± 2.3, SB treated: 29 ± 2.4, p < 0.01). SB-334867 did not attenuate withdrawal syndrome, when it was microinjected as a single dose immediately before naloxone injection. The present results suggest a role for orexin in naloxone-precipitated withdrawal and thus possibly morphine dependence and this effect is, at least in part, via OX1Rs in the dorsal hippocampus.