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Metabotropic glutamate receptor 5 and dorsal raphe serotonin release in inflammatory pain in rat
Enza Palazzo1, Rita Genovese, Loredana Mariani
1Department of Experimental Medicine, Section of Pharmacology "L. Donatelli", Faculty of Medicine and Surgery, II University of Naples, via Costantinopoli 16, 80138 Naples, Italy. enza.palazzo@unina2.it
Abstract:
In this study, we evaluated the effects of 2-methyl-6-(phenylethynyl)-pyridine (MPEP), a selective antagonist of metabotropic glutamate subtype 5 receptors (mGlu(5)), delivered through different paths on dorsal raphe serotonin (5-HT) and on thermoceptive responses in rats with inflammatory pain. Intraplantar formalin and carrageenan increased 5-HT (137+/-11% and 212+/-6% of pre-injection baseline, respectively) and reduced nociceptive threshold (23+/-7% and 19+/-3% of pre-injection baseline, respectively). MPEP (2 mg/kg i.p.) further enhanced formalin and carrageenan-induced 5-HT increases (180+/-11% and 260+/-12% of pre-injection baseline, respectively) and reduced thermal hyperalgesia (71+/-8% and 80+/-10% of pre-injection baseline, respectively). MPEP (1 mM) through microdialytic probe into the dorsal raphe did not change formalin- or carrageenan-induced 5-HT increases (147+/-10% and 189+/-10% of pre-injection baseline, respectively) and thermal hyperalgesia (35+/-8% and 25+/-9% of pre-injection baseline, respectively). Finally, MPEP (30 nmol/rat) into the hind paw reduced the formalin- and carrageenan-induced 5-HT increase (108+/-3% and 126+/-7% of pre-injection baseline, respectively) and thermal hyperalgesia (77+/-6% and 117+/-7% of pre-injection baseline, respectively). Dorsal raphe serotonergic neurons activity increased following a peripherally induced inflammatory injury. In these conditions, peripheral but not dorsal raphe mGlu(5) receptors blockade prevented over activation of dorsal raphe serotonergic neurons and reversed thermal hyperalgesia.
Insights
Blocking peripheral metabotropic glutamate 5 (mGlu5) receptors with MPEP reduced inflammatory pain and dorsal raphe serotonin (5-HT) increases. This suggests peripheral mGlu5 receptors play a key role in inflammatory pain signaling.
Area of Science:
- Neuroscience
- Pharmacology
- Pain Research
Background:
- Inflammatory pain conditions often involve altered serotonin (5-HT) neurotransmission.
- Metabotropic glutamate subtype 5 (mGlu5) receptors are implicated in pain modulation.
Purpose of the Study:
- To investigate the role of peripheral and central mGlu5 receptor antagonism by MPEP on dorsal raphe 5-HT activity and thermal hyperalgesia in inflammatory pain models in rats.
Main Methods:
- Induction of inflammatory pain using formalin and carrageenan injections in rats.
- Administration of MPEP via systemic (i.p.), dorsal raphe (microdialysis), and peripheral (hind paw) routes.
- Measurement of dorsal raphe 5-HT levels and thermal nociceptive threshold.
Main Results:
- Systemic and peripheral MPEP administration enhanced formalin/carrageenan-induced 5-HT increases and reduced thermal hyperalgesia.
- Intra-dorsal raphe MPEP did not alter 5-HT levels or thermal hyperalgesia.
- Peripheral MPEP administration attenuated the increase in dorsal raphe serotonergic neurons and reversed thermal hyperalgesia.
Conclusions:
- Peripheral mGlu5 receptor blockade is effective in mitigating inflammatory pain and associated hyperactivation of dorsal raphe serotonergic neurons.
- Targeting peripheral mGlu5 receptors represents a potential therapeutic strategy for inflammatory pain.
