Loss of neurons in rostral ventromedial medulla that express neurokinin-1 receptors decreases the development of hyperalgesia

Sergey Khasabov, Donald A Simone

Research output: Contribution to journalArticle

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Abstract

It is well known that neurons in the rostral ventromedial medulla (RVM) are involved in descending modulation of nociceptive transmission in the spinal cord. It has been shown that activation of neurokinin-1 receptors (NK-1Rs) in the RVM, which are presumably located on pain facilitating ON cells, produces hyperalgesia whereas blockade of NK-1Rs attenuates hyperalgesia. To obtain a better understanding of the functions of NK-1R expressing neurons in the RVM, we selectively ablated these neurons by injecting the stable analog of substance P (SP), Sar9,Met(O2)11-Substance P, conjugated to the ribosomal toxin saporin (SSP-SAP) into the RVM. Rats received injections of SSP-SAP (1?M) or an equal volume of 1?M of saporin conjugated to artificial peptide (Blank-SAP). Stereological analysis of NK-1R- and NeuN-labeled neurons in the RVM was determined 21-24days after treatment. Withdrawal responses to mechanical and heat stimuli applied to the plantar hindpaw were determined 5-28days after treatment. Withdrawal responses were also determined before and after intraplantar injection of capsaicin (acute hyperalgesia) or complete Freund's adjuvant (CFA) (prolonged hyperalgesia).The proportion of NK-1R-labeled neurons in the RVM was 8.8. ±. 1.3% in naïve rats and 8.1. ±. 0.8% in rats treated with Blank-SAP. However, injection of SSP-SAP into the RVM resulted in a 90% decrease in NK-1R-labeled neurons. SSP-SAP did not alter withdrawal responses to mechanical or heat stimuli under normal conditions, and did not alter analgesia produced by morphine administered into the RVM. In contrast, the duration of nocifensive behaviors produced by capsaicin and mechanical and heat hyperalgesia produced by capsaicin and CFA were decreased in rats pretreated with SSP-SAP as compared to those that received Blank-SAP.These data support our earlier studies using NK-1R antagonists in the RVM and demonstrate that RVM neurons that possess the NK-1R do not play a significant role in modulating acute pain or morphine analgesia, but rather are involved in pain facilitation and the development and maintenance of hyperalgesia.

Original languageEnglish (US)
Pages (from-to)151-165
Number of pages15
JournalNeuroscience
Volume250
DOIs
StatePublished - Sep 16 2013

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Neurokinin-1 Receptors
Hyperalgesia
Neurons
Capsaicin
Freund's Adjuvant
Hot Temperature
Substance P
Analgesia
Morphine
Injections
Pain
Acute Pain
Spinal Cord
Maintenance
Peptides
Therapeutics

Keywords

  • Capsaicin
  • Descending facilitation
  • Inflammation
  • ON cells
  • Pain modulation
  • Saporin

Cite this

Loss of neurons in rostral ventromedial medulla that express neurokinin-1 receptors decreases the development of hyperalgesia. / Khasabov, Sergey; Simone, Donald A.

In: Neuroscience, Vol. 250, 16.09.2013, p. 151-165.

Research output: Contribution to journalArticle

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abstract = "It is well known that neurons in the rostral ventromedial medulla (RVM) are involved in descending modulation of nociceptive transmission in the spinal cord. It has been shown that activation of neurokinin-1 receptors (NK-1Rs) in the RVM, which are presumably located on pain facilitating ON cells, produces hyperalgesia whereas blockade of NK-1Rs attenuates hyperalgesia. To obtain a better understanding of the functions of NK-1R expressing neurons in the RVM, we selectively ablated these neurons by injecting the stable analog of substance P (SP), Sar9,Met(O2)11-Substance P, conjugated to the ribosomal toxin saporin (SSP-SAP) into the RVM. Rats received injections of SSP-SAP (1?M) or an equal volume of 1?M of saporin conjugated to artificial peptide (Blank-SAP). Stereological analysis of NK-1R- and NeuN-labeled neurons in the RVM was determined 21-24days after treatment. Withdrawal responses to mechanical and heat stimuli applied to the plantar hindpaw were determined 5-28days after treatment. Withdrawal responses were also determined before and after intraplantar injection of capsaicin (acute hyperalgesia) or complete Freund's adjuvant (CFA) (prolonged hyperalgesia).The proportion of NK-1R-labeled neurons in the RVM was 8.8. ±. 1.3{\%} in na{\"i}ve rats and 8.1. ±. 0.8{\%} in rats treated with Blank-SAP. However, injection of SSP-SAP into the RVM resulted in a 90{\%} decrease in NK-1R-labeled neurons. SSP-SAP did not alter withdrawal responses to mechanical or heat stimuli under normal conditions, and did not alter analgesia produced by morphine administered into the RVM. In contrast, the duration of nocifensive behaviors produced by capsaicin and mechanical and heat hyperalgesia produced by capsaicin and CFA were decreased in rats pretreated with SSP-SAP as compared to those that received Blank-SAP.These data support our earlier studies using NK-1R antagonists in the RVM and demonstrate that RVM neurons that possess the NK-1R do not play a significant role in modulating acute pain or morphine analgesia, but rather are involved in pain facilitation and the development and maintenance of hyperalgesia.",
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