In:
Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 109, No. 2 ( 2012-01-10)
Abstract:
The effects of SP that we show are essentially opposite the role that SP previously has been proposed to play. Many pharmaceutical companies have developed NK1 antagonist programs based on the idea that SP signaling promotes pain ( 5 ). Given the specific antinociceptive effect of SP on muscle nociceptors, NK1 receptor antagonists actually might worsen muscle pain, compromising their clinical efficacy in treating pain. Our finding offers insight for ongoing clinical trials testing NK1 antagonists in fibromyalgia patients. In particular, blocking SP–NK1 signaling might increase the risk of muscle-originated, chronic hyperalgesia. In contrast, local application of SP might relieve muscle pain. Thus, we uncovered an unexpected antinociceptive role for SP in muscle nociceptors that involves an unconventional NK1 signal pathway. Intramuscular release of SP seems to play an important physiological role in nociceptive plasticity by limiting the acid-induced referred and mirror-image hyperalgesia to a transient effect. The antinociceptive effect of SP seems to be mediated by reducing acid-induced depolarization occurring through ion channels in ASIC3-expressing muscle nociceptors. Our results suggest a model in which activation of acid-sensitive muscle nociceptors triggers the local release of SP, and the local release of SP attenuates acid-induced depolarization by triggering an M channel-like activity ( Fig. P1 ). The effect involves NK1 receptors and a tyrosine kinase but not G proteins. SP causes a slow inactivating outward current ( I SP-O ) in these muscle nociceptors. The I SP-O hyperpolarizes muscle nociceptors and thus can reduce acid-induced inward current and pain. Therefore we next examined the downstream effectors of SP signaling. This outward current is blocked by antagonists to NK1 and, unlike other G protein-coupled receptors, is not decreased substantially after repeated SP administration. Similar to the SP effect on ASIC3-mediated current, the I SP-O current is not altered by GDP-β-S, again suggesting that G proteins do not play a role in the SP signaling. Moreover, I SP-O is blocked by inhibitors of tyrosine kinases (important enzymes that add phosphorous-signaling molecules to tyrosine residues of other proteins) and is enhanced by a reagent that inhibits the removal of phosphorous molecules. This result suggests the involvement of protein tyrosine kinase. We further demonstrated that the downstream effector of this I SP-O current is an M-type potassium channel. Selective M-channel blockers significantly inhibit I SP-O . Consistent with these in vitro data, coinjection of acid with M-channel blockers into muscle produces a hyperalgesic effect, similar to the effect of the NK1 antagonist. To probe the antinociceptive role of SP in muscles, we used electrophysiological recordings to examine whether SP affects acid-induced cell depolarization in muscle nociceptors. We found that SP selectively reduces the acid-induced inward current in ASIC3-expressing muscle nociceptors but not in other sensory neurons. This cell-type–specific effect relies on neurokinin 1 (NK1) receptors, normally known as “G protein-coupled receptors.” However, the effect of SP on ASIC3-mediated current was resistant to GDP-β-S dialysis, indicating that NK1 receptors are involved but G protein is not. Ion channels play a crucial role in neuronal signaling and activation by allowing neuron polarization to change. Some of these channels respond to changes in acid levels, and one such channel—acid-sensing ion channel 3 (ASIC3)—has been found to be necessary for the development of muscle pain ( 3 ). Further studies have suggested a role for SP in pain sensitivity ( 4 ). SP is a small protein generated in pain receptor neurons (or nociceptors) and released in response to painful stimulation. As described by Sluka et al. ( 2 , 3 ), an acid injection into the muscle of a hind limb causes referred hyperalgesia in the hind paw on the same side and a mirror image of hyperalgesia in the paw on the opposite site. Referred and mirror-image hyperalgesia decreased after 24 h in normal or wild-type mice but persisted for a long time when SP receptors in the injected muscle were blocked or when SP signaling was disrupted. Muscle pain that occurs in common disorders such as ischemia (poor blood flow) and fibromyalgia (a condition of widespread pain) can pose a significant clinical problem, but the reasons for this pain are not fully understood ( 1 ). Studies have shown that dual intramuscular injections of an acidic solution spaced 5 d apart lead to chronic (or long-lasting) hyperalgesia, [i.e., extreme pain sensitivity ( 2 )], but the f ull mechanisms have yet to be elucidated completely. Here, we evaluated the role of a neurotransmitter (a molecule involved in transmission of signals between neurons) called “substance P” (SP) in the development of hyperalgesia following repeated injections of an acidic solution into muscles. We identified an antinociceptive (pain-reducing) effect of SP that contradicts current assumptions made in anti-pain drug research.
Type of Medium:
Online Resource
ISSN:
0027-8424
,
1091-6490
DOI:
10.1073/pnas.1108903108
Language:
English
Publisher:
Proceedings of the National Academy of Sciences
Publication Date:
2012
detail.hit.zdb_id:
209104-5
detail.hit.zdb_id:
1461794-8
SSG:
11
SSG:
12
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