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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

Department of Anesthesia, Stanford University, Palo Alto, California, United States
Pain (Impact Factor: 5.21). 05/2006; 121(3):232-40. DOI: 10.1016/j.pain.2005.12.026
Source: PubMed

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.

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    • "After baseline nociceptive testing, morphine (Sigma Chemical, St. Louis, MO) was subcutaneously administered to mice on an escalating dose starting from 10 mg/kg up to 40 mg/kg twice per day for 4 days (Figure 1A) in 50–100 μl volumes of 0.9% NaCl as previously described [18, 19, 22]. "
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    ABSTRACT: Background The long term use of opioids for the treatment of pain leads to a group of maladaptations which includes opioid-induced hyperalgesia (OIH). OIH typically resolves within few days after cessation of morphine treatment in mice but is prolonged for weeks if histone deacetylase (HDAC) activity is inhibited during opioid treatment. The present work seeks to identify gene targets supporting the epigenetic effects responsible for OIH prolongation. Results Mice were treated with morphine according to an ascending dose protocol. Some mice also received the selective HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) additionally. Chronic morphine treatment with simultaneous HDAC inhibition enhanced OIH, and several spinal cord genes were up-regulated. The expression of Bdnf (Brain-derived neurotrophic factor) and Pdyn (Prodynorphin) were most closely related to the observed behavioral changes. ChIP (Chromatin immuoprecipation) assays demonstrated that promoter regions of Pdyn and Bdnf were strongly associated with aceH3K9 (Acetylated histone H3 Lysine9) after morphine and SAHA treatment. Furthermore, morphine treatment caused an increase in spinal BDNF and dynorphin levels, and these levels were further increased in SAHA treated mice. The selective TrkB (tropomyosin-receptor-kinase) antagonist ANA-12 reduced OIH when given one or seven days after cessation of morphine. Treatment with the selective kappa opioid receptor antagonist nor-BNI also reduced established OIH. The co-administration of either receptor antagonist agent daily with morphine resulted in attenuation of hyperalgesia present one day after cessation of treatment. Additionally, repeated morphine exposure induced a rise in BDNF expression that was associated with an increased number of BDNF+ cells in the spinal cord dorsal horn, showing strong co-localization with aceH3K9 in neuronal cells. Lastly, spinal application of low dose BDNF or Dynorphin A after resolution of OIH produced mechanical hypersensitivity, with no effect in controls. Conclusions The present study identified two genes whose expression is regulated by epigenetic mechanisms during morphine exposure. Treatments aimed at preventing the acetylation of histones or blocking BDNF and dynorphin signaling may reduce OIH and improve long-term pain using opioids.
    Full-text · Article · Sep 2014 · Molecular Pain
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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. "
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    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.
    Full-text · Article · Jun 2014 · Behavioural pharmacology
    • "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. "
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    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
    No preview · Article · Jan 2014 · Behavioural Pharmacology
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