title: Changes in the rewarding effects induced by tramadol and its active metabolite M1 after sciatic nerve injury in mice.
abstract: BACKGROUND
  The present study was designed to investigate the rewarding effects induced by tramadol and its active metabolite O-desmethyltramadol (M1) under a neuropathic pain-like state.
  
  
  RESULTS
  In opioid receptor binding and G protein activation, we confirmed that M1, but not tramadol, showed mu-opioid receptor (MOR) agonistic activity. Furthermore, we found that the subcutaneous (s.c.) injection of tramadol and M1 each produced a significant place preference in mice, and these effects were significantly suppressed by pretreatment with the MOR antagonist beta-funaltrexamine. The dopamine level in the mouse nucleus accumbens was significantly increased by s.c. injection of either tramadol or M1. Mice with sciatic nerve ligation exhibited a marked decrease in the latency of paw withdrawal in response to a thermal stimulus only on the ipsilateral side. Under these neuropathic pain-like conditions, the rewarding effect induced by s.c. injection of either tramadol or M1 was dramatically inhibited after sciatic nerve ligation. Furthermore, the M1-induced G protein activation in the lower midbrain area was suppressed after sciatic nerve ligation.
  
  
  CONCLUSIONS
  Our present data support the notion that the rewarding effect induced by tramadol is mediated mainly through metabolism to its active metabolite M1 via MOR. Furthermore, the suppression of the M1-induced G protein activation in the lower midbrain area caused by sciatic nerve ligation may be responsible for inhibiting the rewarding effects induced by s.c. injection of tramadol and M1 under a neuropathic pain-like state.
authors.affiliation: Department of Toxicology, School of Pharmacy and Pharmaceutical Sciences, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Nakamura
authors.forename: Minoru
authors.initials: M
authors.lastname: Narita
authors.forename: Kan
authors.initials: K
authors.lastname: Miyoshi
authors.forename: Keiko
authors.initials: K
authors.lastname: Shindo
authors.forename: Daiki
authors.initials: D
authors.lastname: Okutsu
authors.forename: Masami
authors.initials: M
authors.lastname: Suzuki
authors.forename: Kimio
authors.initials: K
authors.lastname: Higashiyama
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Suzuki