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Periaqueductal gray matter metabotropic glutamate receptors modulate formalin-induced nociception
S Maione1, P Oliva, I Marabese
1Institute of Pharmacology and Toxicology, Faculty of Medicine and Surgery, The Second University of Naples, Via Costantinopoli 16, 80138, Naples, Italy.
Abstract:
The role played by periaqueductal gray (PAG) matter metabotropic glutamate receptors (mGluRs) in the modulation of persistent noxious stimulation was investigated in mice. The formalin test was used as a model of persistent pain. Intra-PAG microinjections of (S)-3, 5-DHPG (25 and 50 nmol/mouse) and L-CCG-I (30 and 60 nmol/mouse), agonists of group I and group II mGluRs, respectively, decreased the nociceptive response (-92+/-6% and -89+/-8%, respectively) during the late phase. No change of the early nociceptive phase was observed after (S)-3,5-DHPG or L-CCG-I treatments. These effects were antagonized by a pretreatment with CPCCOEt (40 nmol/mouse) and (2S)-alpha-EGlu (30 nmol/mouse). CPCCOEt is a selective antagonist of group I mGlu receptors, while (2S)-alpha-EGlu is an antagonist of group II. Intra-PAG microinjections of L-SOP (60 and 120 nmol/mouse), a selective agonist of group III mGluRs, induced an increase of the nociceptive response (+95+/-7%) during the late hyperalgesic phase. (R,S)-alpha-M-SOP (70 nmol/mouse), a selective antagonist of group III mGluRs, completely antagonized the L-SOP-induced effect. These results show that PAG mGluRs participate in modulating the late hyperalgesic behaviours induced by formalin. It seems, therefore, possible that group I and group II mGluRs positively modulate PAG antinociceptive descending pathway following a persistent noxious stimulation, while group III mGluRs modulate it negatively.
Insights
Metabotropic glutamate receptors (mGluRs) in the periaqueductal gray (PAG) modulate persistent pain. Group I and II mGluRs reduce pain, while Group III mGluRs enhance it, suggesting differential roles in pain pathways.
Area of Science:
- Neuroscience
- Pain Research
- Pharmacology
Background:
- The periaqueductal gray (PAG) is a key area for pain modulation.
- Metabotropic glutamate receptors (mGluRs) are implicated in various neurological functions, including pain signaling.
Purpose of the Study:
- To investigate the role of different mGluR groups within the PAG in modulating persistent pain using a mouse model.
- To determine the specific effects of group I, II, and III mGluR activation and antagonism on nociceptive responses.
Main Methods:
- Utilized the formalin test in mice to model persistent pain.
- Administered selective agonists and antagonists of mGluR groups (I, II, and III) via microinjection into the PAG.
- Quantified nociceptive responses during the early and late phases of the formalin test.
Main Results:
- Activation of group I and II mGluRs in the PAG significantly reduced late-phase nociception, an effect blocked by specific antagonists.
- (S)-3,5-DHPG and L-CCG-I (group I and II agonists) decreased pain by over 89% during the late phase.
- Activation of group III mGluRs (L-SOP) increased late-phase nociception, an effect blocked by its antagonist ((R,S)-alpha-M-SOP).
Conclusions:
- PAG mGluRs play a crucial role in modulating persistent pain responses.
- Group I and II mGluRs in the PAG positively modulate descending antinociceptive pathways.
- Group III mGluRs in the PAG negatively modulate these descending pain pathways.