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The Role of Peptides in Central Sensitization

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Book cover Sensory Nerves

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 194))

Abstract

Peptides released in the spinal cord from the central terminals of nociceptors contribute to the persistent hyperalgesia that defines the clinical experience of chronic pain. Using substance P (SP) and calcitonin gene-related peptide (CGRP) as examples, this review addresses the multiple mechanisms through which peptidergic neurotransmission contributes to the development and maintenance of chronic pain. Activation of CGRP receptors on terminals of primary afferent neurons facilitates transmitter release and receptors on spinal neurons increases glutamate activation of AMPA receptors. Both effects are mediated by cAMP-dependent mechanisms. Substance P activates neurokinin receptors (3 subtypes) which couple to phospholipase C and the generation of the intracellular messengers whose downstream effects include depolarizing the membrane and facilitating the function of AMPA and NMDA receptors. Activation of neurokinin-1 receptors also increases the synthesis of prostaglandins whereas activation of neurokinin-3 receptors increases the synthesis of nitric oxide. Both products act as retrograde messengers across synapses and facilitate nociceptive signaling in the spinal cord. Whereas these cellular effects of CGRP and SP at the level of the spinal cord contribute to the development of increased synaptic strength between nociceptors and spinal neurons in the pathway for pain, the different intracellular signaling pathways also activate different transcription factors. The activated transcription factors initiate changes in the expression of genes that contribute to long-term changes in the excitability of spinal and maintain hyperalgesia.

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Abbreviations

AMPA:

α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionate

cAMP:

Cyclic AMP

CaMK:

Ca2+/calmodulin-dependent protein kinase

CGRP:

Calcitonin gene-related peptide

COX:

Cyclo-oxygenase

CRE:

Cyclic AMP response element

CREB:

Cyclic AMP response element binding protein

CRLR:

Calcitonin receptor-like receptor

ERK:

Extracellular-signal-regulated kinase

mRNA:

Messenger RNA

NFAT:

Nuclear factor of activated T cells

NK1:

Neurokinin 1

NK2:

Neurokinin 2

NK3:

Neurokinin 3

NKA:

Neurokinin A

NKB:

Neurokinin B

NOS:

Nitric oxide synthase

NSAID:

Nonsteroidal anti-inflammatory drug

pCREB:

Phosphorylated cyclic AMP response element binding protein

PGE2:

Prostaglandin E2

PPT-A:

Preprotachykinin A

RAMP:

Receptor activity modifying protein

RCP:

Receptor component protein

SP:

Substance P

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Authors and Affiliations

  1. Department of Neuroscience, University of Minnesota, 6-145 Jackson Hall, 321 Church St., S.E., Minneapolis, MN, 55455, USA

    V.S. Seybold

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  1. V.S. Seybold
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Correspondence to V.S. Seybold .

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Editors and Affiliations

  1. Dept. Medicine, Johns Hopkins Asthma & Allergy Center, Hopkins Bayview Circle 5501, Baltimore, 21224, U.S.A.

    Brendan J. Canning

  2. School of Biomedical & Health Sciences, King's College London, Guy's Campus, London, SE1 9RT, United Kingdom

    Domenico Spina

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Seybold, V. (2009). The Role of Peptides in Central Sensitization. In: Canning, B., Spina, D. (eds) Sensory Nerves. Handbook of Experimental Pharmacology, vol 194. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-540-79090-7_13

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