Antibodies directed against the mu-opioid receptor alleviated multiple signs of morphine withdrawal in mice

Abstract

An investigation was made into the effect of intracerebroventricular (i.c.v.) administration of antibodies to the amino-terminal portion 1–16 (MDSSTGPGNTSDCSDP) or the peptide sequence 208–216 (TKYRQGSID) of the cloned μ-opioid receptor (μ-OR) on morphine tolerance and dependence. Animals were rendered tolerant-dependent by subcutaneous (s.c.) implantation of an oily morphine suspension. To precipitate withdrawal syndrome, the opioid antagonist naloxone (1 mg kg , s.c.) was administered 72 h after chronic morphine treatment. In mice i.c.v. injected with the anti-μ-OR antibodies, the analgesic effect of chronic morphine was significantly reduced. These antibodies given 24 h before starting the chronic morphine treatment, reduced most of the symptoms associated with the withdrawal syndrome (jumps, loss of body weight, diarrhoea and body shakes) elicited by naloxone in dependent mice. The administration of the antisera to mice undergoing 48 h of chronic morphine treatment did not precipitate detectable signs of abstinence, but reduced the withdrawal syndrome precipitated by naloxone 24 h later. The finding that both antibodies impaired μ 1 μ 2 - mediated effects, suggests a high degree of homology between the pharmacologically defined subtypes of μ-OR.