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

Abstract

Intraplantar injection of 0.4% formalin into the rat hind paw leads to a biphasic nociceptive response; an 'acute' phase (0-15 min) and 'tonic' phase (16-120 min), which is accompanied by significant phosphorylation of extracellular signalregulated kinase (ERK)1/2 in the contralateral striatum at 120 min post-formalin injection. To uncover a possible relationship between the slow-onset substance P (SP) release and increased ERK1/2 phosphorylation in the striatum, continuous infusion of SP into the striatum by reverse microdialysis (0.4 lg/mL in microdialysis fiber, 1 lL/min) was performed to mimic volume neurotransmission of SP. Continuous infusion for 3 h of SP reduced the duration of 'tonic' phase nociception, and this SP effect was mediated by neurokinin 1 (NK1) receptors since pre-treatment with NK1 receptor antagonist CP96345 (10 lM) blocked the effect of SP infusion. However, formalin-induced 'tonic' phase nociception was significantly prolonged following acute injection of the MAP/ERK kinase 1/2 inhibitor PD0325901 (100 pmol) by microinjection. The coinfusion of SP and PD0325901 significantly increased the 'tonic' phase of nociception. These data demonstrate that volume transmission of striatal SP triggered by peripheral nociceptive stimulation does not lead to pain facilitation but a significant decrease of tonic nociception by the activation of the SP-NK1 receptor-ERK1/2 system.

The Striosome and Matrix Compartments of the Striatum: A Path through the Labyrinth from Neurochemistry toward Function

“…The neuropeptide SP also has significant scope for compartment-specific function, including an action on DA transmission. SP is produced and released by D1R-expressing MSNs and is enriched in the striosomes. ,− Neurokinin-1-receptors (NK1Rs), which are the principal target receptor for SP, are expressed throughout the striatum but somewhat paradoxically are at higher density in the matrix, predominantly on nitric-oxide synthase-expressing GABAergic interneurons (NOS interneurons), somatostatin-positive interneurons (SST-positive), and ChIs. − This mismatch in expression between SP and its NK1R has also been reported in other brain regions and likely reflects a role of SP as a volume transmitter with actions at sites remote from release. , SP is not known to be taken back up into neurons, and no SP-specific peptidase has yet been identified that could catabolize SP to limit the spread of its function (although AChE has been shown to hydrolyze SP in vitro ). − …”

“…59−62 This mismatch in expression between SP and its NK1R has also been reported in other brain regions and likely reflects a role of SP as a volume transmitter with actions at sites remote from release. 60,63 SP is not known to be taken back up into neurons, and no SP-specific peptidase has yet been identified that could catabolize SP to limit the spread of its function (although AChE has been shown to hydrolyze SP in vitro). 63−65 We recently revisited the action of SP on striatal DA to explore whether previous contradictory findings could be attributed to a striosome−matrix compartmentalization.…”

Intracellular emetic signaling cascades by which the selective neurokinin type 1 receptor (NK1R) agonist GR73632 evokes vomiting in the least shrew (Cryptotis parva)

“…administration of diverse emetogens (Zhong et al, 2016, 2014b). Furthermore, phosphorylation of ERK1/2 has been shown to play an important role in diverse NK 1 R-mediated cellular responses (Amadoro et al, 2007; Lallemend et al, 2003; Nakamura et al, 2014; Ramnath et al, 2007). However, NK 1 R belongs to the large family of GPCRs and signals through several different pathways associated with distinct G proteins (Garcia-Recio and Gascón, 2015).…”

A Chitosan—Based Liposome Formulation Enhances the In Vitro Wound Healing Efficacy of Substance P Neuropeptide

“…This caveat might be circumvented by a suitable formulation able to control the payload release. Indeed, a study found evidence that continuous infusion of SP into the striatum of rats alleviates pain by decreasing nociception rather than inducing it [ 27 ]. These reasons suggest that it may be desirable to develop a carrier system to enhance SP’s pharmacokinetic and pharmacodynamic parameters.…”