Dorsal striatum metabotropic glutamate receptor 8 affects nocifensive responses and rostral ventromedial medulla cell activity in neuropathic pain conditions

Abstract

In SNI rats, which showed a reduction of the mechanical withdrawal threshold, intra-DS microinjection of (S)-3,4-DCPG inhibited the ongoing and tail flick-evoked activity of the ON cells while increasing the activity of the OFF cells. AZ12216052, a selective mGluR 8 positive allosteric modulator (PAM), behaved like (S)-3,4-DCPG in increasing tail flick latency and OFF cell activity and decreasing ON cell activity in SNI rats only but was less potent. VU0155041, a selective mGluR 4 PAM, was ineffective in changing thermal nociception and ON and OFF cell activity in both shamoperated and SNI rats. (S)-3,4-DCPG did not change mechanical withdrawal threshold in sham-operated rats but increased it in SNI rats. Furthermore, a decreased level of mGluR 8 gene and immunoreactivity, expressed on GABAergic terminals, associated with a protein increase was found in the DS of SNI rats. These results suggest that stimulation of mGluR 8 inhibits thermoceptive responses and mechanical allodynia. These effects were associated with inhibition of ON cells and stimulation of OFF cells within RVM. metabotropic glutamate receptor subtype 8; spared nerve injury; dorsal striatum; rostral ventromedial medulla; mechanical allodynia NEUROPATHIC PAIN, which is often resistant to conventional analgesics (Sindrup and Jensen 1999;Woolf and Mannion 1999), remains a significant clinical problem. After peripheral or central nervous system injury, spinal and brain plastic changes lead to central sensitization and consequent thermal hyperalgesia and mechanical allodynia symptoms (Chudler and Dong 1995;Hagelberg et al.

Rostral ventromedial medulla‐mediated descending facilitation following P2X7 receptor activation is involved in the development of chronic post‐operative pain

“…Two types of neurons in the RVM, the so-called ON and OFF cells, are involved in the modulation of nociception at the spinal level (Fields et al 1991(Fields et al , 1995. In various pain models, including diabetes, chronic constriction injury, spared nerve injury, formalin, and carrageenan pain models, the spontaneous activity of pain facilitatory ON cells in the RVM is increased, whereas the spontaneous activity of the pain inhibitory OFF cells is decreased (de Novellis et al 2005;Palazzo et al 2011aPalazzo et al ,b, 2012Silva et al 2013;Rossi et al 2014;Marabese et al 2018). The decrease in the spontaneous activity of OFF cells indicates that the tonic pain inhibition exerted by RVM neurons is lost under the pain state.…”

Nociception modulation by supraspinal group III metabotropic glutamate receptors

“…Local injections of VU015504 into the dorsal striatum in sham and neuropathic rats failed to change the tail flick latency or activity of the ON and OFF cells of the rostral ventromedial medulla (RVM) (Rossi et al . ). ON cells are excited by nociceptive stimuli and inhibited by centrally acting analgesics, whereas OFF cells are inhibited by noxious stimuli and activated by analgesics.…”

Continuous infusion of substance P into rat striatum alleviates nociceptive behavior via phosphorylation of extracellular signal‐regulated kinase 1/2

“…; Rossi et al . ). These observations raise the distinct possibility that a NK1R and ERK1/2 phosphorylation‐dependent mechanism modulate the RVM pain facilitatory pathway.…”

“…In the mouse brain, axons from the striatum directly project to the RVM (Wall et al 2013). In addition, studies utilizing models of neuropathic pain have shown that striatal neurons directly modulate activity of RVM neurons involved in descending pain modulation (Barcel o et al 2010;Rossi et al 2013). These observations raise the distinct possibility that a NK1R and ERK1/2 phosphorylation-dependent mechanism modulate the RVM pain facilitatory pathway.…”

“…In contrast, patients with a neurodegenerative disorder involving the basal ganglia, such as Parkinson's disease, and traumatic brain injury and stroke involving the striatum show symptoms of various painful disorders including dystonia, radiculopathy, and central neuropathic pain (Goto et al 2008;Beiske et al 2009;Boivie 2009;Ford 2009;Letro et al 2009;Bugnicourt et al 2011). Moreover, rodent studies show that microinjection of excitatory amino acids, catecholamines, and neuropeptides into the striatum leads to anti-nociceptive effects in animal models of neuropathic pain and formalin-induced nociception (Magnusson and Fisher 2000;Gear and Levine 2009;Barcel o et al 2012;Nakamura et al 2013;Rossi et al 2013;Li et al 2014). Thus, the striatum is involved in not only the modulation of motor functioning but also significantly involved in nociceptive processing.…”