Mechanisms of Bv8-induced biphasic hyperalgesia: Increased excitatory transmitter release and expression

Milena De Felice, Pietro Melchiorri, Michael H. Ossipov, Todd W Vanderah, Frank Porreca, Lucia Negri

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Bv8 is a pronociceptive peptide that binds to two G-protein coupled prokineticin receptors, PK-R1 and PK-R2. These receptors are localized in the dorsal horn of the spinal cord and dorsal root ganglia (DRG) of nociceptive neurons in rodents. Systemic administration of Bv8 elicits a biphasic reduction in nociceptive thresholds to thermal and mechanical stimuli. Here, the possibility that Bv8 might directly modulate the expression and release of excitatory transmitters within the early and late phases of hyperalgesia was evaluated. Administration of Bv8 to mouse lumbar spinal cord sections produced a direct, significant and concentration-related release of CGRP. Bv8- or capsaicin-stimulated CGRP release was markedly enhanced in tissues taken from Bv8-pretreated mice during the late, but not the early, phase of hyperalgesia. Pretreatment of rats with protein synthesis inhibitors blocked the expression of the late, but not early, phase of Bv8-induced hyperalgesia. Finally, during the late-phase of hyperalgesia, there was an upregulation of CGRP and substance P immunoreactivity in the rat lumbar dorsal horn and DRG. Such upregulation was prevented by pretreatment with protein synthesis inhibitors. These data suggest that Bv8 induces hyperalgesia by direct release of excitatory transmitters in the spinal cord, consistent with the first phase of hyperalgesia. Additionally, Bv8 elicits a subsequent, protein-synthesis dependent increase in expression and release of excitatory transmitters that may underlie the long-lasting second phase of hyperalgesia. Activation of prokineticin receptors may therefore contribute to persistent hyperalgesia occurring as a consequence of tissue injury further suggesting that these receptors are attractive targets for development of therapeutics for pain treatment.

Original languageEnglish (US)
Pages (from-to)40-45
Number of pages6
JournalNeuroscience Letters
Volume521
Issue number1
DOIs
StatePublished - Jul 11 2012

Fingerprint

Hyperalgesia
Spinal Cord
Protein Synthesis Inhibitors
Spinal Ganglia
Up-Regulation
Nociceptors
Spinal Nerve Roots
Capsaicin
Substance P
G-Protein-Coupled Receptors
Rodentia
Hot Temperature
Pain
Peptides
Wounds and Injuries
Therapeutics

Keywords

  • CGRP
  • Prokineticin receptors
  • Prokineticins
  • Sensitization

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Mechanisms of Bv8-induced biphasic hyperalgesia : Increased excitatory transmitter release and expression. / De Felice, Milena; Melchiorri, Pietro; Ossipov, Michael H.; Vanderah, Todd W; Porreca, Frank; Negri, Lucia.

In: Neuroscience Letters, Vol. 521, No. 1, 11.07.2012, p. 40-45.

Research output: Contribution to journalArticle

De Felice, Milena ; Melchiorri, Pietro ; Ossipov, Michael H. ; Vanderah, Todd W ; Porreca, Frank ; Negri, Lucia. / Mechanisms of Bv8-induced biphasic hyperalgesia : Increased excitatory transmitter release and expression. In: Neuroscience Letters. 2012 ; Vol. 521, No. 1. pp. 40-45.
@article{55aaffe213a4435d88350cec05e59280,
title = "Mechanisms of Bv8-induced biphasic hyperalgesia: Increased excitatory transmitter release and expression",
abstract = "Bv8 is a pronociceptive peptide that binds to two G-protein coupled prokineticin receptors, PK-R1 and PK-R2. These receptors are localized in the dorsal horn of the spinal cord and dorsal root ganglia (DRG) of nociceptive neurons in rodents. Systemic administration of Bv8 elicits a biphasic reduction in nociceptive thresholds to thermal and mechanical stimuli. Here, the possibility that Bv8 might directly modulate the expression and release of excitatory transmitters within the early and late phases of hyperalgesia was evaluated. Administration of Bv8 to mouse lumbar spinal cord sections produced a direct, significant and concentration-related release of CGRP. Bv8- or capsaicin-stimulated CGRP release was markedly enhanced in tissues taken from Bv8-pretreated mice during the late, but not the early, phase of hyperalgesia. Pretreatment of rats with protein synthesis inhibitors blocked the expression of the late, but not early, phase of Bv8-induced hyperalgesia. Finally, during the late-phase of hyperalgesia, there was an upregulation of CGRP and substance P immunoreactivity in the rat lumbar dorsal horn and DRG. Such upregulation was prevented by pretreatment with protein synthesis inhibitors. These data suggest that Bv8 induces hyperalgesia by direct release of excitatory transmitters in the spinal cord, consistent with the first phase of hyperalgesia. Additionally, Bv8 elicits a subsequent, protein-synthesis dependent increase in expression and release of excitatory transmitters that may underlie the long-lasting second phase of hyperalgesia. Activation of prokineticin receptors may therefore contribute to persistent hyperalgesia occurring as a consequence of tissue injury further suggesting that these receptors are attractive targets for development of therapeutics for pain treatment.",
keywords = "CGRP, Prokineticin receptors, Prokineticins, Sensitization",
author = "{De Felice}, Milena and Pietro Melchiorri and Ossipov, {Michael H.} and Vanderah, {Todd W} and Frank Porreca and Lucia Negri",
year = "2012",
month = "7",
day = "11",
doi = "10.1016/j.neulet.2012.05.055",
language = "English (US)",
volume = "521",
pages = "40--45",
journal = "Neuroscience Letters",
issn = "0304-3940",
publisher = "Elsevier Ireland Ltd",
number = "1",

}

TY - JOUR

T1 - Mechanisms of Bv8-induced biphasic hyperalgesia

T2 - Increased excitatory transmitter release and expression

AU - De Felice, Milena

AU - Melchiorri, Pietro

AU - Ossipov, Michael H.

AU - Vanderah, Todd W

AU - Porreca, Frank

AU - Negri, Lucia

PY - 2012/7/11

Y1 - 2012/7/11

N2 - Bv8 is a pronociceptive peptide that binds to two G-protein coupled prokineticin receptors, PK-R1 and PK-R2. These receptors are localized in the dorsal horn of the spinal cord and dorsal root ganglia (DRG) of nociceptive neurons in rodents. Systemic administration of Bv8 elicits a biphasic reduction in nociceptive thresholds to thermal and mechanical stimuli. Here, the possibility that Bv8 might directly modulate the expression and release of excitatory transmitters within the early and late phases of hyperalgesia was evaluated. Administration of Bv8 to mouse lumbar spinal cord sections produced a direct, significant and concentration-related release of CGRP. Bv8- or capsaicin-stimulated CGRP release was markedly enhanced in tissues taken from Bv8-pretreated mice during the late, but not the early, phase of hyperalgesia. Pretreatment of rats with protein synthesis inhibitors blocked the expression of the late, but not early, phase of Bv8-induced hyperalgesia. Finally, during the late-phase of hyperalgesia, there was an upregulation of CGRP and substance P immunoreactivity in the rat lumbar dorsal horn and DRG. Such upregulation was prevented by pretreatment with protein synthesis inhibitors. These data suggest that Bv8 induces hyperalgesia by direct release of excitatory transmitters in the spinal cord, consistent with the first phase of hyperalgesia. Additionally, Bv8 elicits a subsequent, protein-synthesis dependent increase in expression and release of excitatory transmitters that may underlie the long-lasting second phase of hyperalgesia. Activation of prokineticin receptors may therefore contribute to persistent hyperalgesia occurring as a consequence of tissue injury further suggesting that these receptors are attractive targets for development of therapeutics for pain treatment.

AB - Bv8 is a pronociceptive peptide that binds to two G-protein coupled prokineticin receptors, PK-R1 and PK-R2. These receptors are localized in the dorsal horn of the spinal cord and dorsal root ganglia (DRG) of nociceptive neurons in rodents. Systemic administration of Bv8 elicits a biphasic reduction in nociceptive thresholds to thermal and mechanical stimuli. Here, the possibility that Bv8 might directly modulate the expression and release of excitatory transmitters within the early and late phases of hyperalgesia was evaluated. Administration of Bv8 to mouse lumbar spinal cord sections produced a direct, significant and concentration-related release of CGRP. Bv8- or capsaicin-stimulated CGRP release was markedly enhanced in tissues taken from Bv8-pretreated mice during the late, but not the early, phase of hyperalgesia. Pretreatment of rats with protein synthesis inhibitors blocked the expression of the late, but not early, phase of Bv8-induced hyperalgesia. Finally, during the late-phase of hyperalgesia, there was an upregulation of CGRP and substance P immunoreactivity in the rat lumbar dorsal horn and DRG. Such upregulation was prevented by pretreatment with protein synthesis inhibitors. These data suggest that Bv8 induces hyperalgesia by direct release of excitatory transmitters in the spinal cord, consistent with the first phase of hyperalgesia. Additionally, Bv8 elicits a subsequent, protein-synthesis dependent increase in expression and release of excitatory transmitters that may underlie the long-lasting second phase of hyperalgesia. Activation of prokineticin receptors may therefore contribute to persistent hyperalgesia occurring as a consequence of tissue injury further suggesting that these receptors are attractive targets for development of therapeutics for pain treatment.

KW - CGRP

KW - Prokineticin receptors

KW - Prokineticins

KW - Sensitization

UR - http://www.scopus.com/inward/record.url?scp=84862618445&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84862618445&partnerID=8YFLogxK

U2 - 10.1016/j.neulet.2012.05.055

DO - 10.1016/j.neulet.2012.05.055

M3 - Article

C2 - 22641053

AN - SCOPUS:84862618445

VL - 521

SP - 40

EP - 45

JO - Neuroscience Letters

JF - Neuroscience Letters

SN - 0304-3940

IS - 1

ER -