Toll-like receptor 4 mutant and null mice retain morphine-induced tolerance, hyperalgesia, and physical dependence.
The innate immune system modulates opioid-induced effects within the central nervous system and one target that has received considerable attention is the toll-like receptor 4 (TLR4). Here, we examined the contribution of TLR4 in the development of morphine tolerance, hyperalgesia, and physical dependence in two inbred mouse strains: C3H/HeJ mice which have a dominant negative point mutation in the Tlr4 gene rendering the receptor non-functional, and B10ScNJ mice which are TLR4 null mutants. We found that neither acute antinociceptive response to a single dose of morphine, nor the development of analgesic tolerance to repeated morphine treatment, was affected by TLR4 genotype. Likewise, opioid induced hyperalgesia and opioid physical dependence (assessed by naloxone precipitated withdrawal) were not altered in TLR4 mutant or null mice. We also examined the behavioural consequence of two stereoisomers of naloxone: (-) naloxone, an opioid receptor antagonist, and (+) naloxone, a purported antagonist of TLR4. Both stereoisomers of naloxone suppressed opioid induced hyperalgesia in wild-type control, TLR4 mutant, and TLR4 null mice. Collectively, our data suggest that TLR4 is not required for opioid-induced analgesic tolerance, hyperalgesia, or physical dependence.
Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada.
Theresa Alexandra
TA
Mattioli
Departments of Comparative Biology & Experimental Medicine, Physiology & Pharmacology, Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.
Heather
H
Leduc-Pessah
Department of Pathology and Molecular Medicine, Queen's University, Kingston, Ontario, Canada; Cancer Biology and Genetics Division, Cancer Research Institute, Queen's University, Kingston, Ontario, Canada.
Graham
G
Skelhorne-Gross
Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada; Department of Pathology and Molecular Medicine, Queen's University, Kingston, Ontario, Canada; Cancer Biology and Genetics Division, Cancer Research Institute, Queen's University, Kingston, Ontario, Canada.
Chris J B
CJ
Nicol
Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada; Department of Anaesthesiology & Perioperative Medicine, Queen's University, Kingston, Ontario, Canada.
Brian
B
Milne
Departments of Comparative Biology & Experimental Medicine, Physiology & Pharmacology, Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.
Tuan
T
Trang
Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada; Department of Anesthesiology and Perioperative Care, University of California Irvine, Irvine, California, United States of America.
Catherine M
CM
Cahill
D000818:Animals; D017931:DNA Primers / Q000235:genetics; D004361:Drug Tolerance / Q000502:physiology*; D006930:Hyperalgesia / Q000139:chemically induced* / Q000188:drug therapy; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009020:Morphine / Q000009:adverse effects*; D009021:Morphine Dependence / Q000209:etiology / Q000503:physiopathology*; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D017354:Point Mutation / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors / Q000235:genetics*
D017931:DNA Primers; D009292:Narcotic Antagonists; D051197:Toll-Like Receptor 4; D009270:Naloxone; D009020:Morphine