Changes in the rewarding effects induced by tramadol and its active metabolite M1 after sciatic nerve injury in mice
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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.
In opioid receptor binding and G protein activation, we confirmed that M1, but not tramadol, showed μ-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 β-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.
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.
KeywordsTramadol Active metabolite M1 Rewarding effect Neuropathic pain Opioid receptor binding G protein activation Nucleus accumbens Ventral tegmental area Dopamine μ-Opioid receptor
This work was supported in part by grants from the Ministry of Health, Labor and Welfare and the Ministry of Education, Culture, Sports, Science and Technology of Japan.
Disclosure/conflict of interest
The authors declare that, except for the income received from their primary employer, no financial support or compensation has been received from any individual or corporate entity over the past 3 years for research or professional service and there are no personal financial holdings that could be perceived as constituting a potential conflict of interest.
- Imai S, Narita M, Hashimoto S, Nakamura A, Miyoshi K, Nozaki H, Hareyama N, Takagi T, Suzuki M, Narita M, Suzuki T (2006) Differences in tolerance to anti-hyperalgesic effects between chronic treatment with morphine and fentanyl under the pain-like state. Japanese Journal of Psychopharmacology 26:183–192PubMedGoogle Scholar
- Narita M, Nakamura A, Ozaki M, Imai S, Miyoshi K, Suzuki M, Suzuki T (2007) Comparative pharmacological profiles of morphine and oxycodone under a neuropathic pain-like state in mice: evidence for less sensitivity to morphine. Neuropsycopharmacology 33:1097–1112Google Scholar
- Ozaki S, Narita M, Narita M, Iino M, Sugita J, Matsumura Y, Suzuki T (2002) Suppression of the morphine-induced rewarding effect in the rat with neuropathic pain: implication of the reduction in m-opioid receptor functions in the ventral tegmental area. J Neurochem 82:1192–1198PubMedCrossRefGoogle Scholar
- Ozaki S, Narita M, Narita M, Iino M, Miyoshi K, Suzuki T (2003) Suppression of the morphine-induced rewarding effect and G-protein activation in the lower midbrain following nerve injury in the mouse: involvement of G-protein-coupled receptor kinase2. Neuroscience 116:89–97PubMedCrossRefGoogle Scholar
- Paxinos G, Franklin KBJ (2001) The mouse brain in stereotaxic coordinates, 2nd edn. Academic, San DiegoGoogle Scholar
- Suzuki T (1996) Conditioned place preference in mice. Methods Find Exp Clin Pharmacol 18:75–83Google Scholar
- WHO Expert Committee on Drug Dependence (2006) World Health Organ Tech Rep Ser 942:1–21, 23–24Google Scholar