Possible antinociceptive mechanisms of opioid receptor antagonists in the mouse formalin test

It has been reported that opioid receptor antagonist can induce antinociception in several nociceptive tests. In the intraplantar formalin pain model, however, opioid antagonist-induced antinociception, as well as its underlying mechanism, has not been well characterized. Therefore, in the mouse formalin test, we attempted to characterize the site of action and the possible opioid receptor subtypes. We found that naltrexone (a nonselective opioid antagonist) injected intraperitoneally (ip, 1–20 mg/kg), intrathecally (it, 0.1–10 μg) and intracerebroventricularly (icv, 0.1–10 μg) inhibited nociceptive behaviors only during the second phase (20–40 min) but not during the first (0–5 min) phase. Administration of β-funaltrexamine (β-FNA, 10–40 mg/kg ip, 1.25–5 μg it or icv), naltrindole (1–10 mg/kg ip, 1.25–5 μg it or icv) and nor-binaltorphimine (nor-BNI, 1–10 mg/kg ip, 10–40 μg it or icv), which are selective μ-, δ- and κ-opioid antagonists, respectively, also produced antinociception during the second phase. Additionally, we examined the involvement of the descending monoaminergic systems in the naltrexone-induced antinociception in the formalin test. Pretreatment with 5,7-dihydroxytryptamine (5,7-DHT, a serotonergic neurotoxin, 20 μg it), but not N-(2-chloroethyl)- N-ethyl-2-bromobenzylamine (DSP-4, a noradrenergic neurotoxin, 20 μg it), reversed the naltrexone-induced antinociception during the second phase. Our results suggest that blockade of supraspinally or spinally located opioid receptors may play roles in the regulation of antinociception during the tonic painful stage. In addition, opioid receptors localized at the neuroterminal of the descending serotonergic, but not noradrenergic, inhibitory system in the spinal cord appear to be involved in opioid antagonist-induced antinociception during the second tonic phase of the formalin test.