An antinociceptive role for substance P in acid-induced chronic muscle pain

Abstract

Release of substance P (SP) from nociceptive nerve fibers and activation of its receptor neurokinin 1 (NK1) are important effectors in the transmission of pain signals. Nonetheless, the role of SP in muscle pain remains unknown. Here we show that a single i.m. acid injection in mice lacking SP signaling by deletion of the tachykinin precursor 1 (Tac1) gene or coadministration of NK1 receptor antagonists produces long-lasting hyperalgesia rather than the transient hyperalgesia seen in control animals. The inhibitory effect of SP was found exclusively in neurons expressing acid-sensing ion channel 3, where SP enhances M-channel-like potassium currents through the NK1 receptor in a G protein-independent but tyrosine kinase-dependent manner. Furthermore, the SP signaling could alter action potential thresholds and modulate the expression of TTX-resistant sodium currents in medium-sized muscle nociceptors. Thus, i.m. SP mediates an unconventional NK1 receptor signal pathway to inhibit acid activation in muscle nociceptors, resulting in an unexpected antinociceptive effect against chronic mechanical hyperalgesia, here induced by repeated i.m. acid injection.is an undecapeptide belonging to the tachykinin small-peptide family (1). SP is generated in primary nociceptive sensory neurons (nociceptors) and is released with noxious stimulation (2). The release from cutaneous peripheral terminals induces neurogenic inflammation and release from central terminals enhances the glutamate-dependent excitatory postsynaptic potential, thus leading to central sensitization (3-5). Although sensory neurons in muscle also contain SP, i.m. SP injection evokes a very low level of neurogenic inflammation and no pain (6, 7).Accumulating evidence has suggested that muscle pain might be closely related to acidosis and activation of proton-sensing ion channels (8-10). Lactate and ATP sensitize this acid activation (11,12). Human and animal studies have revealed that acidosis is an effective trigger of muscle pain. Thus, chronic muscle pain can be induced in rodents by repeated i.m. injection of acid (13,14), by i.m. injection of complete Freund's adjuvant (CFA), carrageenan, capsaicin, or proinflammatory cytokines (15-18), by arterial occlusion (19), and by eccentric muscle contraction (20). These stimuli might correspond to muscle pain related to acidosis, inflammatory and ischemic myalgia, or delayed-onset muscle soreness. Although these models might not reflect fully the complicated human pain conditions, and although repetitive acidosis is not known to produce chronic pain or central sensitization in humans, these rodent models are useful for probing the underlying mechanisms and analgesic modulation of chronic muscle pain. For instance, acid-sensing ion channel 3 (ASIC3) is essential for triggering acid-induced mechanical hyperalgesia in models of i.m. injection of acid, CFA, or carrageenan (13,17,(21)(22)(23). Coinjection of neurotrophin-3 reverses the acid-induced chronic hyperalgesia (24). Also, some muscle-derived pain can be attenu...

Reactive oxygen species are second messengers of neurokinin signaling in peripheral sensory neurons

“…However, during the proteolytic dissociation of DRG neurons, M current is inhibited by the protease-activated receptor PAR-2 (22) and also by high cytosolic Ca 2+ levels (52) that are unavoidable in acutely dissociated neurons; therefore, the effect of SP on M current is most likely underestimated in acutely dissociated neurons. Recently SP has been reported to enhance an XE991-sensitive current in a proportion of muscle afferent neurons through an Src kinasedependent, GPCR-independent mechanism (53). Although M-current enhancement by SP is consistent with the present study, the signaling cascade is not.…”

Molecular and cellular mechanisms that initiate pain and itch

“…Peripheral NK1R also mediates SP-induced anti-nociceptive effects on acid-induced chronic muscle pain by enhancing activity of the M-type K + channels [159]. These studies suggest that NK1R is a versatile pain modulator that can either enhance or attenuate pain response through activation of distinct downstream signaling pathways.…”

Acid-sensing ion channels (ASICs): therapeutic targets for neurological diseases and their regulation

“…Replacing GTP with a non-hydrolysable analog in the internal pipette solution, had no effects on the inhibition of ASIC3-mediated currents by substance P (99). However, ASIC3-mediated currents were significantly diminished by a bath application of genistein, a phosphotyrosine kinase (PTK) inhibitor (99). Furthermore, M channel-like activity is also involved in the antinociceptive effect of substance P. During tissue acidosis in the muscle, ASIC3 channels are activated by protons, and depolarize the muscle afferent neurons, resulting in the firing of action potentials and the release of substance P. Substance P activates NK 1 receptors, and the activation of NK 1 receptors leads to the unconventional pathway, which activates tyrosine kinase and the M channel in the muscle afferent neurons.…”

“…Mice, lacking substance P and neurokinin A production by disrupting the tachykinin 1 (Tac1) gene or injection of a selective NK1 receptor antagonist, displayed persistent long-lasting hyperalgesia (99). Substance P significantly reduced ASIC3-mediated currents in muscle afferent DRG neurons.…”