Abstract
We investigated whether chronic sciatic ligation modifies the glutamate release in spinal cord nerve endings (synaptosomes) as well as the expression and the function of presynaptic release-regulating mGlu2/3 autoreceptors and 5-HT2A heteroreceptors in these particles. Synaptosomes were from the spinal cord of animals suffering from the sciatic ligation that developed on day 6 post-surgery a significant decrease of the force inducing paw-withdrawal in the lesioned paw. The exocytosis of glutamate (quantified as release of preloaded [3H]D-aspartate, [3H]D-Asp) elicited by a mild depolarizing stimulus (15 mM KCl) was significantly increased in synaptosomes from injured rats when compared to controls (uninjured rats). The mGlu2/3 agonist LY379268 (1000 pM) significantly inhibited the 15 mM KCl-evoked [3H]D-Asp overflow from control synaptosomes, but not in terminals isolated from injured animals. Differently, a low concentration (10 nM) of (±) DOI, unable to modify the 15 mM KCl-evoked [3H]D-Asp overflow in control spinal cord synaptosomes, significantly reduced the glutamate exocytosis in nerve endings isolated from the injured rats. Acute oral trazodone (TZD, 0.3 mg/kg on day 7 post-surgery) efficiently recovered glutamate exocytosis as well as the efficiency of LY379268 in inhibiting this event in spinal cord synaptosomes from injured animals. The sciatic ligation significantly reduced the expression of mGlu2/3, but not of 5-HT2A, receptor proteins in spinal cord synaptosomal lysates. Acute TZD recovered this parameter. Our results support the use of 5-HT2A antagonists for restoring altered spinal cord glutamate plasticity in rats suffering from sciatic ligation.
Highlights
Metabotropic glutamate receptors are fine tuners of the chemical transmission in the central nervous system (CNS) and represent the target of drugs proposed for the cure of neurological disorders
The present study aims at investigating whether the expression and the functions of the presynaptic release-regulating mGlu2/3 and serotonin type 2A (5-HT2A) receptors in spinal cord glutamatergic nerve endings are altered in animal suffering from the chronic sciatic ligation and if oral acute trazodone could impact mGlu2/3 functions recovering the altered glutamate exocytosis
Glutamate exocytosis was quantified as 15 mM KCl-evoked overflow of preloaded [3H]D-aspartate ([3H]D-Asp), a nonmetabolizable glutamate analogue routinely used as a marker of the endogenous aminoacid in release studies (Grilli et al, 2004; Di Prisco et al, 2012; Di Prisco et al, 2016)
Summary
Metabotropic glutamate (mGlu) receptors are fine tuners of the chemical transmission in the central nervous system (CNS) and represent the target of drugs proposed for the cure of neurological disorders. Naïve mGlu receptors exist as homodimers, as intra- (i.e. the mGlu1/mGlu and the mGlu2/3 receptor dimers, Longordo et al, 2006; Di Prisco et al, 2016) or inter-group heteromeric complexes (the mGlu2/mGlu heterodimers, Doumazane et al, 2010, the mGlu5/mGlu complex, Di Menna et al, 2018), or oligomerize with nonglutamatergic G protein coupled receptors to form inter-family heteromeric assemblies It is the case of the 5-HT2A/mGlu2/3 receptor-receptor complex in the cortex and in the spinal cord of mammals, of the mGlu1/GABAB receptor-receptor interaction in GABAergic and glutamatergic cortical terminals and of the mGlu5/A2A receptor-receptor association in the striatum (Dıá zCabiale et al, 2002; Moreno et al, 2011; Moreno et al, 2012; Delille et al, 2012; Vergassola et al, 2018). The present study aims at investigating whether the expression and the functions of the presynaptic release-regulating mGlu2/3 and 5-HT2A receptors in spinal cord glutamatergic nerve endings (we refer to as synaptosomes) are altered in animal suffering from the chronic sciatic ligation and if oral acute trazodone could impact mGlu2/3 functions recovering the altered glutamate exocytosis
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