(251) A Time Course of the Development of Hyperalgesia during Spontaneous Withdrawal in NIH Swiss Mice

Abstract

Pain patients may experience heightened sensitivity to pain while trying to discontinue opioid use which may contribute to resumption of opioid use in order to avoid more pain. However, most studies in animals that investigate hyperalgesia during opioid withdrawal focus on hyperalgesia during precipitated opioid withdrawal and include only male animals. The present study was conducted to assess hyperalgesia during a protracted withdrawal state in female and male NIH Swiss mice. Mice were rendered opioid-dependent by twice daily s.c. injections of morphine in escalating doses (50-125 mg/kg) or saline vehicle for four consecutive days; there was a final dose of morphine on day 5. Body weight was taken prior to injections as well as mornings and evenings prior to testing. Paw withdrawal thresholds to increasing paw pressures were recorded prior to the first injection and at 5, 10, 24, 34, 48, 58, 72, 82, 96 and 106 h after the final injection. Mice consistently lost weight during morphine administration; however, both sexes gained weight immediately following cessation of drug treatment. Morphine-dependent animals exhibited pronounced hyperalgesia starting at 10 h after the final morphine injection and subsiding at roughly 58 h for females and 82 h for males. A main effect of morphine administration showed that animals that received morphine had significantly reduced paw withdrawal thresholds in percentage of baseline. A main effect of sex indicates that males had generally lower scores over time than females in hyperalgesia data. These results indicate that spontaneous withdrawal causes hyperalgesia in NIH Swiss mice. This is significant because while it is known that withdrawal can cause hyperalgesia, most animal models that investigate this phenomenon use a precipitated withdrawal model, while our study demonstrated hyperalgesia also occurs in a spontaneous withdrawal model. This research was supported in part by State of Washington Initiative Measure 171. Pain patients may experience heightened sensitivity to pain while trying to discontinue opioid use which may contribute to resumption of opioid use in order to avoid more pain. However, most studies in animals that investigate hyperalgesia during opioid withdrawal focus on hyperalgesia during precipitated opioid withdrawal and include only male animals. The present study was conducted to assess hyperalgesia during a protracted withdrawal state in female and male NIH Swiss mice. Mice were rendered opioid-dependent by twice daily s.c. injections of morphine in escalating doses (50-125 mg/kg) or saline vehicle for four consecutive days; there was a final dose of morphine on day 5. Body weight was taken prior to injections as well as mornings and evenings prior to testing. Paw withdrawal thresholds to increasing paw pressures were recorded prior to the first injection and at 5, 10, 24, 34, 48, 58, 72, 82, 96 and 106 h after the final injection. Mice consistently lost weight during morphine administration; however, both sexes gained weight immediately following cessation of drug treatment. Morphine-dependent animals exhibited pronounced hyperalgesia starting at 10 h after the final morphine injection and subsiding at roughly 58 h for females and 82 h for males. A main effect of morphine administration showed that animals that received morphine had significantly reduced paw withdrawal thresholds in percentage of baseline. A main effect of sex indicates that males had generally lower scores over time than females in hyperalgesia data. These results indicate that spontaneous withdrawal causes hyperalgesia in NIH Swiss mice. This is significant because while it is known that withdrawal can cause hyperalgesia, most animal models that investigate this phenomenon use a precipitated withdrawal model, while our study demonstrated hyperalgesia also occurs in a spontaneous withdrawal model. This research was supported in part by State of Washington Initiative Measure 171.