Liang DY, Guo T, Liao G, Kingery WS, Peltz G, Clark JD .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.
- SourceAvailable from: Enrique Portillo-Salido
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- "Morphine was the most potent analgesic in both inflammatory pain models. These results are in agreement with previous data reporting increased paw withdrawal latencies to heat and mechanical stimuli after systemic administration of opioids in the same animal models (Luger et al., 2002; Lähdesmäki et al., 2003; Bileviciute-Ljungar et al., 2006; Liang et al., 2006; Ortiz et al., 2007). The nonselective COX inhibitor ibuprofen showed higher potency than the selective COX-2 inhibitor celecoxib in both inflammatory models. "
ABSTRACT: The therapeutic potential of S1RA (E-52862), a selective sigma-1 receptor (σ1R) antagonist, has been explored in experimental neuropathic pain, but not in inflammatory pain models. The present study investigated the effect of the intraperitoneal administration of S1RA on the hind paw withdrawal response to thermal and mechanical stimulation following an intraplantar injection of carrageenan (CARR) and complete Freund's adjuvant (CFA), which are two well-characterized models of acute and chronic inflammatory pain, respectively. S1RA fully reversed both mechanical [dose of drug that produced half of its maximal response (ED50)=35.9 and 42.1 mg/kg for CARR-induced and CFA-induced pain, respectively] and thermal (ED50=27.9 mg/kg, CARR) hypersensitivity, whereas ibuprofen (CARR, mechanical allodynia) and celecoxib (CARR, thermal hyperalgesia; CFA, mechanical allodynia) failed to reach maximum efficacy. Morphine also showed maximum efficacy in all tests. Unlike celecoxib and ibuprofen, which decreased paw volume significantly, CARR-induced paw oedema was not reduced by S1RA and morphine, thus suggesting that the antinociceptive effect of S1RA does not involve a major anti-inflammatory (antioedema) action. S1RA was devoid of efficacy when administered to σ1R knockout mice, thus suggesting the involvement of σ1R in the antinociceptive effects exerted by S1RA. We conclude that S1RA represents a promising novel analgesic therapy for inflammatory pain.Behavioural pharmacology 06/2014; 25(3):226-35. DOI:10.1097/FBP.0000000000000038 · 2.19 Impact Factor
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- "The finding that daily administration did not decrease the analgesic effects of oxycodone was unexpected given the abundance of preclinical findings demonstrating profound induction of tolerance to mu-opioid agonists. However, despite the large body of preclinical literature pointing to this phenomenon, there are reports demonstrating that under a variety of paradigms, tolerance to opioid-induced analgesia is dependent upon a number of factors including dose, duration, and interdose interval of opioid administration, as well as genetic factors and the presence of pre-existing pain (e.g., Cox and Tiffany, 1997; Mas et al., 2000; Javan et al., 2005; Liang et al., 2006). Although tolerance to the analgesic effects of oxycodone was not observed under the given experimental parameters, one should be cautious in generalizing these present results to more extended opioid dosing schedules. "
ABSTRACT: Tolerance to the analgesic effects of opioids has been demonstrated in laboratory animals after repeated drug administration; yet, this effect has been studied less frequently under controlled laboratory conditions in humans. This within-subject, double-blind, placebo-controlled study was designed to determine whether tolerance developed to the analgesic, subjective, and physiological effects of the commonly prescribed opioid oxycodone when it was administered daily for 5 days. The effects of oxycodone (0, 5, and 20 mg/70 kg, orally) were compared, using a within-session cumulative dosing procedure, on the first and fifth days of the 'daily' dosing phase to assess for tolerance; active oxycodone was administered on the second and fourth days of the daily dosing phase. Changes in the effects of oxycodone were also compared when the medication was only administered on the first and the fifth day of a 5-day 'intermittent' dosing phase; placebo medication was administered on the second and fourth days of the intermittent dosing phase. A 9-day 'washout' period occurred between phases during which no medication was administered. Healthy volunteers (N=10) with no history of drug dependence or current drug use participated in this outpatient study. Analgesia was assessed using the cold pressor test, pain and drug effects were measured using a variety of questionnaires, and pupil diameter was monitored as an index of physiological effects. When administered daily, no differences were observed in oxycodone-induced analgesia between the first and the fifth days, but tolerance did develop to some of the positive subjective effects of oxycodone. In contrast, oxycodone-induced analgesia and participant ratings of some positive subjective drug effects were greater on the fifth compared with the first day of the intermittent dosing phase. No differences in the miotic effects of oxycodone between the first and the fifth days of either dosing phase were detected. Although obtained under limited experimental conditions, these findings suggest that tolerance may not develop to the analgesic effects of therapeutic doses of oxycodone under short-term daily dosing conditions, even though some of its subjective effects may decrease. These data also suggest that intermittent administration may enhance the analgesic effects of oxycodone, while also increasing some of the drug's positive subjective effects related to abuse liability.Behavioural pharmacology 04/2012; 23(3):271-9. DOI:10.1097/FBP.0b013e3283536d6f · 2.19 Impact Factor
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- "Mice provide powerful models for the study of the effects of genetic background and its interaction with the environment in the presence of exogenous substances or averse circumstances or manipulations  , in particular, because each type of mouse is characterized by its peculiar phenotype     . However, even if strain dependence of anxiety related behaviours or nociception has been established    , there is only limited knowledge regarding the relationship between the basal, intrinsic, level of anxiety and the behavioural and molecular impact of painful stimuli in rodents . These complex behaviours are most likely of polygenic nature    and thus confronting inbred, hybrid and outbred mice may offer an important tool as to the relevance of type of genetic background and variance in studying complex behavioural traits. "
ABSTRACT: As in humans, genetic background in rodents may influence a peculiar set of behavioural traits such as sensitivity to pain and stressors or anxiety-related behaviours. Therefore, we tested the hypothesis that mice with different genetic backgrounds [outbred (CD1), inbred (C57BL/6J) and hybrid (B6C3F1) adult male mice] display altered reactivity to pain, stress and anxiety related behaviours. We demonstrated that B6C3F1 mice displayed the more anxious phenotype with respect to C57BL/6J or CD1 animals, with the latter being the less anxious strain when tested in an open field and on an elevated plus maze. No difference was observed across strains in thermal sensitivity to a radiant heat source. Mice were then treated with a sub-plantar injection of the inflammatory agent Complete Freund's Adjuvant (CFA), 24h later they were hyperalgesic with respect to saline exposed animals, irrespective of strain. We then measured intra-strain differences and CFA-induced inter-strain effects on the expression of various genes with a recognized role in pain and anxiety: BDNF, IL-6, IL-1β, IL-18 and NMDA receptor subunits in the mouse thalamus, hippocampus and hypothalamus. The more anxious phenotype observed in B6C3F1 hybrid mice displayed lower levels of BDNF mRNA in the hippocampus and hypothalamus when compared to outbred CD1 and C57BL/6J inbred mice. CFA led to a general decrease in central gene expression of the evaluated targets especially in CD1 mice, while BDNF hypothalamic downregulation stands out as a common effect of CFA in all three strains evaluated.Behavioural brain research 05/2011; 224(1):23-34. DOI:10.1016/j.bbr.2011.05.011 · 3.39 Impact Factor