Substance P and pain chronicity

Abstract

Substance P (SP) is a highly conserved member of the tachykinin peptide family that is widely expressed throughout the animal kingdom. The numerous members of the tachykinin peptide family are involved in a multitude of neuronal signaling pathways, mediating sensations and emotional responses (Steinhoff et al. in Physiol Rev 94:265–301, 2014). In contrast to receptors for classical transmitters, such as glutamate (Parsons et al. in Handb Exp Pharmacol 249–303, 2005), only a minority of neurons in certain brain areas express neurokinin receptors (NKRs) (Mantyh in J Clin Psychiatry 63:6–10, 2002). SP is also expressed by a variety of non-neuronal cell types such as microglia, as well as immune cells (Mashaghi et al. in Cell Mol Life Sci 73:4249–4264, 2016). SP is an 11-amino acid neuropeptide that preferentially activates the neurokinin-1 receptor (NK1R). It transmits nociceptive signals via primary afferent fibers to spinal and brainstem second-order neurons (Cao et al. in Nature 392:390–394, 1998). Compounds that inhibit SP’s action are being investigated as potential drugs to relieve pain. More recently, SP and NKR have gained attention for their role in complex psychiatric processes. It is a key goal in the field of pain research to understand mechanisms involved in the transition between acute pain and chronic pain. The influence of emotional and cognitive inputs and feedbacks from different brain areas makes pain not only a perception but an experience (Zieglgänsberger et al. in CNS Spectr 10:298–308, 2005; Trenkwaldner et al. Sleep Med 31:78–85, 2017). This review focuses on functional neuronal plasticity in spinal dorsal horn neurons as a major relay for nociceptive information.

Atxn2-CAG100-KnockIn mouse spinal cord shows progressive TDP43 pathology associated with cholesterol biosynthesis suppression

“…TACR1 binds substance-P selectively for the sensory perception of itch, pain and inflammation. It is abundant in the spinal cord dorsal horn neurons but is also a component of microglia sensing [28, 241]. Tachykinin levels in the cerebrospinal fluid of ALS patients have been found elevated [119].…”

Novel RvD6 stereoisomer induces corneal nerve regeneration and wound healing post-injury by modulating trigeminal transcriptomic signature

“…The expression of two genes involved in pain was decreased in corneas treated with the RvD6si: Tac1 that encodes SP, which is one of the most abundant neuropeptides expressed in corneal nerves [26][27][28] . SP exerts proinflammatory effects, and preclinical studies linked their action to chronic pain 44 . Besides, Tac1 is upregulated in the TG after corneal injury supporting the finding that corneal nerves "sense" and transmit the inflammatory signal to the TG 45 .…”

The Role of Substance P in Chronic Low Back Pain (CLBP)

“…There are the three main tachykinins in mammals: Substance P, neurokinin A (NKA) and neurokinin B (NKB). Tachykinin family members are distributed in all mammalian tissues and body fluids, but the highest densities of SP are founded in the nervous system both in CNS and the peripheral nervous system [11,48,52,53]. Three area that have the highest densities of SP are in the dorsal horn of the spinal cord, the substantia nigra and the amygdala [11,53].…”

“…The affinity of these neurokinin receptors in binding to substance P is in the order of NK1R > NK2R > NK3R. Substance P preferring NK1R, NKA preferring NK2R and NKB preferring NK3R [11,54]. Substance P is synthesized in the ribosome as a larger protein and then enzymatically converted into the active undecapeptide [55].…”

“…Substance P has an leading role in pain mechanism by mediated central sensitization. The excitability of neurons spinal elevate after escalated afferen activity that implicate in nociception [9][10][11]. Substance P also has an pivotal role in the transition from acute to chronic pain and neurophatic pain mechanism.…”