Time course characteristics of tolerance development to continuously infused antinociceptive agents in rat spinal cord

By using a constant-rate, fixed concentration intrathecal infusion model, the time course of change in hot plate (HP) response latencies over a 7-day period was examined in rats receiving constant infusion of saline (vehicle), morphine (MOR (2, 6 or 20 nmol/hr), sufentanil (SUF) (0.06, 0.2 or 0.6 nmol/hr), D-Ala²-MePhe⁴-Gly-ol⁵-enkephalin (DAMGO) (0.1, 0.3 or 1.0 nmol/hr) (mu opioids), D-Ala²-D-Leu⁵-enkephalin (DADLE) (2, 6 or 20 nmol/hr) (delta opioid), ST-91 (3, 10 or 30 nmol/hr) (alpha-2 agonist) or the combination of ST-91 + MOR. Three important observations were made: 1) A concentration-dependent elevation in HP latency was observed on day 1 (order of potency: DAMGO = SUF > MOR ≥ DADLE ≥ ST-91 + MOR ≥ ST-91) with a gradual return to saline-infused values observed for all concentrations of all drugs by 3 to 5 days. 2) The rate of tolerance development, estimated by calculation of the exponential decay half-life from peak day 1 HP, was not different as a function of drug dose. The area under the 7-day tolerance curve (response latency x day) was directly proportional to infusion concentration and to peak HP effect on day 1. These two calculations both suggest that the rate at which the tolerance adaptation of drug occurs to agonist effects is similar for agents acting upon mu, delta and alpha-2 receptors in rat spinal cord. 3) Plotting the concentration-effect curves observed for days 1 to 4 after infusion revealed that the degree of shift relative to day 1 (ED₅₀ day x/ED₅₀ day 1; x = 1-4) was rank ordered: MOR > ST-91 > DADL >> SUF = DAMGO = ST-91 + MOR. This observation supports the hypothesis that the degree of tolerance (as manifested by the magnitude of the shift over time during continuous infusion) may be dependent upon the receptor reserve or second messengers of that agent in that assay system.