Age-related differences in sensitivity to the antinociceptive effects of opioids in male rats: Influence of nociceptive intensity and intrinsic efficacy at the mu receptor

Despite the widespread popularity of opioid analgesics, significant differences in the potency and effectiveness of these drugs are often observed across age groups. The purpose of this investigation was to examine age-related differences in sensitivity to the antinociceptive effects of mu opioids and to identify the conditions under which these differences are most apparent. In a warm-water tail-withdrawal procedure, young (3 months) and aged (24 months) male rats were habituated to restraint and the latencies to remove their tails from 50 degrees C (low nociceptive intensity) and 55 degrees C (high nociceptive intensity) water were measured. Opioids possessing a range of intrinsic efficacy at the mu receptor (morphine, levorphanol, buprenorphine, butorphanol, nalbuphine, nalorphine) were examined. Young and aged rats were equally sensitive to the antinociceptive effects of morphine, levorphanol, and buprenorphine when tested at the low nociceptive intensity. When these drugs were tested at the high nociceptive intensity, differences between the two age groups became apparent, such that aged rats were significantly more sensitive to the antinociceptive effects of these drugs than young rats. Differences between age groups were most apparent when butorphanol, nalbuphine, and nalorphine were tested, in that each of these drugs produced maximal levels of antinociception in aged rats under conditions in which they failed to produce antinociceptive activity in young rats. Under conditions in which lower efficacy opioids failed to produce antinociceptive activity in young rats, they antagonized the effects of morphine in drug combination tests. These data may be taken as evidence that aged male rats are more sensitive to the antinociceptive effects of mu opioids than young male rats, and that age-related differences in opioid sensitivity are most apparent when lower efficacy opioids and higher nociceptive intensities are employed during behavioral testing.