title: Chronic pain and genetic background interact and influence opioid analgesia, tolerance, and physical dependence.
abstract: Opioids are commonly used in the treatment of moderate to severe pain. However, their chronic use is limited by analgesic tolerance and physical dependence. Few studies have examined how chronic pain affects the development of tolerance or dependence, and essentially no studies have looked at the role of both genetics and pain together. For these studies we used 12 strains of inbred mice. Groups of mice from each strain were tested at baseline for morphine analgesic sensitivity, mechanical nociceptive threshold, and thermal nociceptive threshold. Mice were then given morphine in a 4-day escalating morphine administration paradigm followed by reassessment of the morphine dose-response relationship. Finally, physical dependence was measured by administering naloxone. Parallel groups of mice underwent hind paw injection of complete Freund's adjuvant (CFA) to induce chronic hind paw inflammation 7 days prior to the beginning of testing. The data showed that CFA treatment tended to lower baseline ED(50) values for morphine and enhanced the degree of analgesic tolerance observed after 4 days of morphine treatment. In addition, the degree of jumping behavior indicative of physical dependence was often altered if mice had been treated with CFA. The influence of background strain was substantial for all traits measured. In silico haplotypic mapping of the tolerance and physical dependence data demonstrated that CFA pretreatment altered the pattern of the predicted associations and greatly reduced their statistical significance. We conclude that chronic inflammatory pain and genetics interact to modulate the analgesic potency of morphine, tolerance, and physical dependence.
authors.affiliation: Department of Anesthesia, Stanford University School of Medicine, Stanford, CA, USA Veterans Affairs Palo Alto Healthcare System, Palo Alto, CA, USA Roche Palo Alto, Palo Alto, CA, USA.
authors.forename: De-Yong
authors.initials: DY
authors.lastname: Liang
authors.forename: TianZi
authors.initials: T
authors.lastname: Guo
authors.forename: Guochun
authors.initials: G
authors.lastname: Liao
authors.forename: Wade S
authors.initials: WS
authors.lastname: Kingery
authors.forename: Gary
authors.initials: G
authors.lastname: Peltz
authors.forename: David J
authors.initials: DJ
authors.lastname: Clark
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D002908:Chronic Disease / Q000188:drug therapy; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance / Q000235:genetics / Q000502:physiology; D005620:Freund's Adjuvant / Q000494:pharmacology; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D018836:Inflammation Mediators / Q000494:pharmacology; D008297:Male; D051379:Mice; D008806:Mice, Inbred AKR; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D019463:Mice, Inbred MRL lpr; D009020:Morphine / Q000494:pharmacology; D009270:Naloxone; D009292:Narcotic Antagonists; D009293:Opioid-Related Disorders / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics*; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology*; D013045:Species Specificity
chemical_list: D000701:Analgesics, Opioid; D018836:Inflammation Mediators; D009292:Narcotic Antagonists; D009270:Naloxone; D009020:Morphine; D005620:Freund's Adjuvant