Primary afferent tachykinins are required to experience moderate to intense pain

Abstract

The excitatory neurotransmitter glutamate coexists with the peptide known as substance P in primary afferents that respond to painful stimulation. Because blockers of glutamate receptors reliably reduce pain behaviour, it is assumed that 'pain' messages are mediated by glutamate action on dorsal horn neurons. The contribution of substance P, however, is still unclear. We have now disrupted the mouse preprotachykinin A gene (PPT-A), which encodes substance P and a related tachykinin, neurokinin A. We find that although the behavioural response to mildly painful stimuli is intact in these mice, the response to moderate to intense pain is significantly reduced. Neurogenic inflammation, which results from peripheral release of substance P and neurokinin A, is almost absent in the mutant mice. We conclude that the release of tachykinins from primary afferent pain-sensing receptors (nociceptors) is required to produce moderate to intense pain.

N-Arachidonoyl Dopamine Modulates Acute Systemic Inflammation via Nonhematopoietic TRPV1

“…The nervous system is increasingly being recognized as playing key roles in inflammation, and strong links have been established between the immune and nervous systems. Neurogenic inflammation is believed to be a critical component of inflammatory initiation and the pain response (55,56). There is also strong evidence that the links between the nervous and immune systems are bidirectional, with each able to modulate the activity of the other.…”

Effect of peptidases on the ability of exogenous and endogenous neurokinins to produce neurokinin 1 receptor internalization in the rat spinal cord

“…In contrast, we show here that inhibitors of NEN and DEC produced a relatively smaller increase (2.8 -3.5 times) in the potencies of SP and NKA to produce NK1R internalization. Moreover, whereas peptidase inhibitors are required to observe m-opioid receptor internalization in dorsal horn neurons produced by endogenously released opioids (Song & Marvizon, 2003), endogenously released neurokinins produce abundant NK1R internalization in the absence of peptidase inhibitors (Mantyh et al, 1995;Allen et al, 1997;Liu et al, 1997;Marvizon et al, 1997;1999a;Cao et al, 1998;Honore et al, 1999;Riley et al, 2001). Therefore, it is possible to use peptidase inhibitors to enhance the analgesic effect of endogenous opioids (Noble et al, 1992b;Roques, 2000) without increasing NK1R activation by endogenous neurokinins.…”

“…NK1R activation was measured by their internalization, a technique validated in numerous studies (Mantyh et al, 1995;Allen et al, 1997;Liu et al, 1997;Marvizon et al, 1997;1999a;Cao et al, 1998;Honore et al, 1999;Riley et al, 2001). An additional goal of this study was to compare the potencies of SP, NKA and NKB to produce NK1R internalization.…”

Tachykinins Processing is Significantly Impaired in PC1 and PC2 Mutant Mouse Spinal Cord S9 Fractions

“…Specifically, SP, SP [8][9][10][11] and SP [1][2][3][4][5][6][7] were the most abundant peptide fragments observed. As suggested in Figure 1, C-terminal processing of Tach 20-68 by PC1 or PC2 can lead to the formation of SP.…”

“…RR, RK, KR, KK), followed by the removal of basic amino acids by endopeptidases E (CPE) [1]. The tachykinin precursor 1 (Tac1) gene encodes the protachykinin-1 protein containing the sequence of four tachykinin peptides, including Substance P (SP) and Neurokinin A (NKA) [2]. Besides, the Tac1 gene also encodes other tachykinins, including neuropeptide K (NPK) and neuropeptide γ (NPγ) [3].…”