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Published on: July 29, 2014
Possible antinociceptive mechanisms of opioid receptor antagonists in the mouse formalin test
Seong-Soo Choi1, Ki-Jung Han, Han-Kyu Lee
1Department of Pharmacology, College of Medicine and Institute of Natural Medicine, Hallym University, 1 Okchundong, Chunchon, Kangwon-Do, 200-702, South Korea.
Abstract:
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 (i.p., 1-20 mg/kg), intrathecally (i.t., 0.1-10 microg) and intracerebroventricularly (i.c.v., 0.1-10 microg) phase. Administration of beta-funaltrexamine (beta-FNA, 10-40 mg/kg i.p., 1.25-5 microg it or i.c.v.), naltrindole (1-10 mg/kg i.p., 1.25-5 microg it or i.c.v.) and nor-binaltorphimine (nor-BNI, 1-10 mg/kg i.p., 10-40 microg it or i.c.v.), which are selective mu-, delta- and kappa-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 microg i.t.), but not N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4, a noradrenergic neurotoxin, 20 microg i.t.), 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.
Insights
Opioid receptor antagonists like naltrexone can reduce pain responses in the formalin test. This antinociception involves supraspinal and spinal opioid receptors, particularly those linked to descending serotonergic pathways.
Area of Science:
- Neuroscience
- Pharmacology
- Pain Research
Background:
- Opioid receptor antagonists are known to induce antinociception in various pain models.
- The precise mechanisms and sites of action for opioid antagonists in the formalin pain model remain incompletely understood.
- Characterizing these mechanisms is crucial for understanding pain modulation and potential therapeutic targets.
Purpose of the Study:
- To investigate the site of action and specific opioid receptor subtypes involved in opioid antagonist-induced antinociception.
- To elucidate the role of descending monoaminergic systems in mediating antinociception produced by naltrexone in the formalin test.
Main Methods:
- Utilized the intraplantar formalin test in mice to assess antinociception.
- Administered naltrexone (nonselective opioid antagonist) via intraperitoneal, intrathecal, and intracerebroventricular routes.
- Employed selective opioid receptor antagonists (beta-funaltrexamine, naltrindole, nor-binaltorphimine) and neurotoxins (5,7-DHT, DSP-4) to probe receptor and pathway involvement.
Main Results:
- Naltrexone demonstrated dose-dependent antinociceptive effects when administered systemically, intrathecally, or intracerebroventricularly during the second phase of the formalin test.
- Selective antagonists for mu-, delta-, and kappa-opioid receptors also produced antinociception, indicating involvement of multiple receptor subtypes.
- Pretreatment with the serotonergic neurotoxin 5,7-DHT, but not the noradrenergic neurotoxin DSP-4, reversed naltrexone-induced antinociception.
Conclusions:
- Blockade of supraspinal or spinal opioid receptors contributes to antinociception during the tonic phase of pain in the formalin test.
- Opioid receptors located on the neuroterminal of descending serotonergic, but not noradrenergic, inhibitory pathways in the spinal cord are implicated in this effect.
- These findings highlight the complex role of opioid receptors and descending monoaminergic systems in pain modulation.
