Naloxone acts as a potent analgesic in transgenic mouse models of sickle cell anemia

Mary M. Lunzer, Ajay Yekkirala, Robert P Hebbel, Philip S Portoghese

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Sickle cell anemia is a common genetic disorder in African Americans. Opioid analgesics are traditionally the treatment for the severe pain associated with this disease. Here we reveal that the opioid antagonist naloxone possesses potent analgesic activity in two transgenic mouse models of sickle cell anemia (NY1DD and hBERK1) and not in their respective controls (ICR-CD1 and C57BL/6J) when administered by three parenteral routes [intracerebroventricular (i.c.v.), intrathecal, and subcutaneous]. In the NY1DD mice, naloxone (i.c.v.) possessed ≈300-fold greater potency than morphine (i.c.v.). Other opioid antagonists (naltrexone, norbinaltorphimine, and naltrindole) were substantially less effective in producing analgesia. Naloxone and morphine were synergistic in NY1DD mice, suggesting different receptor systems. Microarray analysis suggested naloxone-induced down-regulation of the CC chemokine receptor (CCR)5 in NY1DD mice but not in control mice. Pretreatment of control mice with CC chemokine ligand 5 [CCL5 (RANTES)] enabled naloxone to produce analgesia similar to that observed in NY1DD mice. Mu opioid receptor knockout mice treated similarly also displayed analgesia. That the effect of CCL5 was specifically related to CCR5 and/or CCR1 activation was demonstrated by antagonism of analgesia with the chemokine antagonist methionylated RANTES. Similar antagonism of naloxone-induced analgesia also was observed when NY1DD mice were pretreated with methionylated RANTES. These results indicate that CCR5/CCR1 receptors are directly or indirectly involved in analgesia produced by naloxone. The present study suggests that naloxone may be clinically useful in the treatment of pain associated with sickle cell disease and other disorders involving inflammation.

Original languageEnglish (US)
Pages (from-to)6061-6065
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number14
DOIs
StatePublished - Apr 3 2007

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Sickle Cell Anemia
Naloxone
Transgenic Mice
Analgesics
Analgesia
Chemokine CCL5
CCR5 Receptors
naltrindole
Narcotic Antagonists
Morphine
CCR1 Receptors
Pain
CC Chemokines
Naltrexone
Inborn Genetic Diseases
mu Opioid Receptor
Microarray Analysis
Chemokines
Knockout Mice
African Americans

Keywords

  • Chemokines
  • Microarray
  • Opioid antagonist

Cite this

Naloxone acts as a potent analgesic in transgenic mouse models of sickle cell anemia. / Lunzer, Mary M.; Yekkirala, Ajay; Hebbel, Robert P; Portoghese, Philip S.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 104, No. 14, 03.04.2007, p. 6061-6065.

Research output: Contribution to journalArticle

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abstract = "Sickle cell anemia is a common genetic disorder in African Americans. Opioid analgesics are traditionally the treatment for the severe pain associated with this disease. Here we reveal that the opioid antagonist naloxone possesses potent analgesic activity in two transgenic mouse models of sickle cell anemia (NY1DD and hBERK1) and not in their respective controls (ICR-CD1 and C57BL/6J) when administered by three parenteral routes [intracerebroventricular (i.c.v.), intrathecal, and subcutaneous]. In the NY1DD mice, naloxone (i.c.v.) possessed ≈300-fold greater potency than morphine (i.c.v.). Other opioid antagonists (naltrexone, norbinaltorphimine, and naltrindole) were substantially less effective in producing analgesia. Naloxone and morphine were synergistic in NY1DD mice, suggesting different receptor systems. Microarray analysis suggested naloxone-induced down-regulation of the CC chemokine receptor (CCR)5 in NY1DD mice but not in control mice. Pretreatment of control mice with CC chemokine ligand 5 [CCL5 (RANTES)] enabled naloxone to produce analgesia similar to that observed in NY1DD mice. Mu opioid receptor knockout mice treated similarly also displayed analgesia. That the effect of CCL5 was specifically related to CCR5 and/or CCR1 activation was demonstrated by antagonism of analgesia with the chemokine antagonist methionylated RANTES. Similar antagonism of naloxone-induced analgesia also was observed when NY1DD mice were pretreated with methionylated RANTES. These results indicate that CCR5/CCR1 receptors are directly or indirectly involved in analgesia produced by naloxone. The present study suggests that naloxone may be clinically useful in the treatment of pain associated with sickle cell disease and other disorders involving inflammation.",
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