title: Low-Dose Cannabinoid Type 2 Receptor Agonist Attenuates Tolerance to Repeated Morphine Administration via Regulating μ-Opioid Receptor Expression in Walker 256 Tumor-Bearing Rats.
abstract: BACKGROUND
  Morphine is widely used in patients with moderate and severe cancer pain, whereas the development of drug tolerance remains a major problem associated with opioid use. Previous studies have shown that cannabinoid type 2 (CB2) receptor agonists induce morphine analgesia, attenuate morphine tolerance in normal and neuropathic pain animals, induce transcription of the μ-opioid receptor (MOR) gene in Jurkat T cells, and increase morphine analgesia in cancer pain animals. However, no studies of the effects of CB2 receptor agonists on morphine tolerance in cancer pain have been performed. Therefore, we investigated the effect of repeated intrathecal (IT) injection of the low-dose CB2 receptor agonist AM1241 on the development of morphine tolerance in walker 256 tumor-bearing rats. We also tested the influence of the CB2 receptor agonist AM1241 on MOR protein and messenger ribonucleic acid (mRNA) expression in the rat spinal cord and dorsal root ganglia (DRG).
  
  
  METHODS
  Walker 256 cells were implanted into the plantar region of each rat's right hindpaw. Tumor-bearing rats received IT injection of the CB2 receptor agonist AM1241 or antagonist AM630 with or without morphine subcutaneously twice daily for 8 days. Rats receiving drug vehicle only served as the control group. Mechanical paw withdrawal threshold and thermal paw withdrawal latency were assessed by a von Frey test and hot plate test 30 minutes after drug administration every day. MOR protein and mRNA expression in the spinal cord and DRG were detected after the last day (day 8) of drug administration via Western blot and real-time reverse transcription polymerase chain reaction. The data were analyzed via analysis of variance followed by Student t test with Bonferroni correction for multiple comparisons.
  
  
  RESULTS
  Repeated morphine treatments reduced the mechanical withdrawal threshold and thermal latency. Coadministration of a nonanalgetic dose of the CB2 receptor agonist AM1241 with morphine significantly inhibited the development of morphine tolerance and increased the MOR protein expression in the spinal cord and DRG and mRNA expression in the spinal cord in tumor-bearing rats.
  
  
  CONCLUSIONS
  Our findings indicate that IT injection of a nonanalgetic dose of a CB2 receptor agonist increased the analgesia effect and alleviated tolerance to morphine in tumor-bearing rats, potentially by regulating MOR expression in the spinal cord and DRG. This receptor may be a new target for prevention of the development of opioid tolerance in cancer pain.
authors.affiliation: From the *Department of Anesthesiology, Cancer Hospital of Harbin Medical University, Harbin, China; †Department of Gynecology, Cancer Hospital of Harbin Medical University, Harbin, China; and ‡Department of Anesthesiology, Cancer Hospital of Harbin Medical University, Pain Research Institute of Heilongjiang Academy of Medical Sciences, Harbin, China.
authors.forename: Mingyue
authors.initials: M
authors.lastname: Zhang
authors.forename: Kun
authors.initials: K
authors.lastname: Wang
authors.forename: Min
authors.initials: M
authors.lastname: Ma
authors.forename: Songyu
authors.initials: S
authors.lastname: Tian
authors.forename: Na
authors.initials: N
authors.lastname: Wei
authors.forename: Guonian
authors.initials: G
authors.lastname: Wang
mesh_terms: D000818:Animals; D002186:Cannabinoids / Q000008:administration & dosage; D002279:Carcinoma 256, Walker / Q000378:metabolism*; D004361:Drug Tolerance; D015972:Gene Expression Regulation, Neoplastic; D006930:Hyperalgesia / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008297:Male; D009020:Morphine / Q000008:administration & dosage*; D051381:Rats; D017208:Rats, Wistar; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists*; D017450:Receptors, Opioid, mu / Q000096:biosynthesis* / Q000235:genetics
chemical_list: C439263:AM 1241; D002186:Cannabinoids; C469526:Cnr2 protein, rat; D043885:Receptor, Cannabinoid, CB2; D017450:Receptors, Opioid, mu; D009020:Morphine