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Mechanisms of Tolerance to delta‐9‐THC in Rodent Models of Pathological Pain
Author(s) -
Morgan Daniel,
Yuill Matthew,
Zee Michael L,
LaFleur Rebecca,
Guindon Josee
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.703.10
Subject(s) - nociception , pharmacology , medicine , drug tolerance , pathological , desensitization (medicine) , pain tolerance , analgesic , morphine , cannabinoid , chronic pain , anesthesia , receptor , threshold of pain , psychiatry
The use of cannabinoids in pain management is of significant interest due to the antinociceptive efficacy of Δ 9 ‐THC. However, tolerance to the antinociceptive effects of Δ 9 ‐THC develops with repeated treatment. The objective of this study was to examine tolerance to daily administration of Δ 9 ‐THC in clinically relevant rodent models of pathological pain. The effects of Δ 9 ‐THC in pathological pain were assessed in male wild‐type and cannabinoid receptor 1 (CB 1 ) desensitization‐resistant S426A/S430A mutant mice. First, we assessed tolerance to Δ 9 ‐THC in mice subjected to the formalin test of inflammatory pain. Intraplantar formalin injection (10 μl at 2.5 %) produces a biphasic nociceptive response consisting of acute and inflammatory pain phases. Experimental groups were subjected to the formalin test after receiving daily intraperitoneal injections of Δ 9 ‐THC (6 mg/kg) ranging from zero to twelve days. Wild‐type mice exhibited complete tolerance to the antinociceptive effects of Δ 9 ‐THC in the formalin test after eight days of daily Δ 9 ‐THC. Interestingly, we find that tolerance to the antinociceptive effects of Δ 9 ‐THC is attenuated in S426A/S430A mutants for the inflammatory pain phase but not for the acute pain phase. The effect of the c‐jun N‐terminal kinase (JNK) inhibitor, SP600125, on Δ 9 ‐THC tolerance was also examined. Pre‐treatment with SP600125 (3 mg/kg) attenuates tolerance for the antinociceptive effects of Δ 9 ‐THC in both the acute and inflammatory pain phases. Tolerance to the anti‐allodynic effects of Δ 9 ‐THC was examined in a mouse model of post‐surgical pain. Injection of Δ 9 ‐THC completely alleviates thermal and mechanical allodynia following a 5 mm hindpaw surgical incision. Consistent with our previous work, tolerance to the anti‐allodynic effects of Δ 9 ‐THC is attenuated in S426A/S430A mutant mice. These results demonstrate that Δ 9 ‐THC exhibits robust antinociceptive effects in two separate rodent models of clinically relevant, pathological pain and are consistent with previous studies showing the attenuation of rapid tolerance to the antinociceptive effects of Δ 9 ‐THC in S426A/S430A mutants using the tail‐flick and hotplate tests. Support or Funding Information Funded by NIH grants DA036385 (DJM), DA037355 (DJM), and Texas Tech University Health Sciences Center School of Medicine 121035 (JG).