Voluntary Running-Wheel Activity, Arterial Blood Gases, and Thermal Antinociception in Rats after 3 Buprenorphine Formulations

Abstract

Buprenorphine HCl (BUP) is a μ-opioid agonist used in laboratory rodents. New formulations of buprenorphine (for example, sustained-released buprenorphine [BUP SR], extended-release buprenorphine [BUP ER]) have been developed to extend the analgesic duration. In a crossover design, 8 adult rats were injected subcutaneously with either BUP, BUP SR, BUP ER, or saline, after which voluntary running-wheel activity, arterial blood gases, and thermal withdrawal latency were assessed. Wheel running was decreased at 24 h compared with baseline in all treatment groups but returned to baseline by 48 h. Arterial pH, HCO3(-), and CO2 were not changed between groups or over time. However, arterial oxygen was lower than baseline in the BUP (-8 ± 2 mm Hg), BUP SR (-7 ± 1 mm Hg), and BUP ER (-17 ± 2 mm Hg) groups compared with saline controls (3 ± 2 mm Hg); the BUP ER group showed the greatest decrease when all time points were combined. BUP increased the withdrawal latency at 1 h (15% ± 3%), whereas BUP ER increased latencies at 4, 8, 12, and 48 h (35% ± 11%, 21% ± 7%, 26% ± 7%, and 22% ± 9%, respectively) and BUP SR prolonged latencies at 24, 48, and 72 h (15% ± 6%, 18% ± 5%, and 20% ± 8%, respectively). The duration of thermal analgesia varied between buprenorphine formulations, but all 3 formulations reduced voluntary-running activity at 24 h after injection and might cause hypoxemia in normal adult rats.

Figure 1.

Effects of saline (control), BUP, BUP SR, and BUP ER on the percentage change from baseline (time 0) in the number of voluntarily run wheel revolutions. There were no significant differences between treatments. However, at 1 d after injection, rats ran significantly less than at baseline; running distance returned to preinjection levels by 48 h after treatment. *, P < 0.05 compared with the values at baseline and 72 h.

Figure 2.

Effects of saline (control), BUP, BUP SR, and BUP ER on the absolute change from baseline (time 0) in arterial pH, HCO₃^–, PaCO₂, and PaO₂. Neither arterial pH, HCO₃^–, nor PaCO₂ differed over time or between groups. PaO₂ values were higher in rats that received saline but lower in those that received BUP ER when compared with all other groups; however, there were no time effects. *, P < 0.05 for saline group compared with BUP, BUP SR, and BUP ER groups; #, P < 0.05 for BUP ER group compared with saline, BUP, and BUP SR groups.

Figure 3.

Effects of saline (control), BUP, BUP SR, and BUP ER on the percentage change from baseline (time 0) in thermal withdrawal latency. In the BUP group, withdrawal latency at 1 h was increased compared with baseline and with that in saline controls at 1 h. Compared with baseline levels, BUP SR increased latencies at 24, 48, and 72 h, but the BUP SR and saline groups did not differ at these time points. Within the BUP SR group, withdrawal latency at 1 h after injection was significantly shorter than those at 8 to 72 h after injection. BUP ER increased withdrawal times from baseline and compared with those of the saline group at 4, 8, 12, 24, and 48 h after treatment. Latencies at 4 to 48 h significantly differed from that at the 1-h time point in the BUP ER group. a, P < 0.050 compared with baseline (time 0) within the same treatment group; b, P < 0.05 compared with 1 h after injection time point within the same treatment group; c, P < 0.05 compared with 4 h after injection within the same treatment group; *, P < 0.05 compared with saline group at the same time point; ×, P < 0.05 compared with all other treatment groups at the same time point; #, P < 0.05 compared with BUP group at the same time point.