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

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.Abbreviations: BUP, buprenorphine hydrochloride; BUP SR, sustained-release buprenorphine; BUP ER, extended-release buprenorphineBuprenorphine HCl (BUP), a synthetic opiate first synthesized in the late 1960s, has been used extensively in laboratory rodents for many years.⁸ The antinociceptive effects of BUP are mediated via actions at the μ-opioid receptor, although the drug has been classified as both a full- and a partial μ-opiate receptor agonist.²⁶ BUP administration is associated with minimal toxicity in rodents because its therapeutic index is at least 3 times greater than that of morphine in animals.⁷ BUP produces minimal to modest respiratory depression, quantified by using arterial blood gas evaluation, even at excessive intravenous doses (3 to 90 mg/kg).^9,16 The analgesic efficacy of BUP has been assessed in several models of acute and chronic pain in rodents.^4,15 Although efficacious in some models, BUP''s duration of action frequently requires repeated postoperative dosing,²⁴ which can reduce body weight and food consumption and affect ambient locomotor activity, thus complicating the ability to use these parameters as signs of postoperative pain.² In addition, the repeated postoperative handling of rats necessary to redose BUP itself may increase animal stress and further contribute to decreases in postoperative weight gain and food intake.^6,14,28 In addition, repeated postoperative dosing of BUP is associated with hyperalgesia, which may limit its usefulness in chronically painful animals.⁶To reduce the negative side effects associated with repeated dosing of BUP, new formulations of BUP (for example, sustained-released buprenorphine [BUP SR], extended-release buprenorphine [BUP ER]) have become available recently with the potential to produce long-lasting analgesia. For example, a single dose of BUP SR has shown analgesic efficacy for as long as 72 h in thermal, incisional, and orthopedic pain models in rats.^5,11 In addition, BUP ER can achieve thermal analgesia in rats for 5 d; however, data are limited on this formulation due to its novelty (commercially released for rats in 2014).¹ These long-lasting formulations may reduce the amount of postoperative animal handling required for multiple injections as well as the associated negative effects. However, no studies have directly evaluated the consequences of these new formulations on important postoperative factors, such as voluntary activity.²Respiratory depression, manifest as arterial hypercapnia, is commonly associated with pure mu-opioid agonists in rats.⁹ However, BUP administration appears to have a “ceiling” effect on ventilation, where a maximum effect is seen despite increases in dose.⁹ Although respiratory rate has been used to estimate opioid-induced respiratory impairment in some models,¹⁰ other studies confirm respiratory rate is not an accurate assessment of ventilation due to subsequent changes in tidal volume and dead space ventilation;²⁹ arterial blood gas analysis is the gold standard to detect hypoventilation using arterial carbon dioxide levels.¹⁹ To the author''s knowledge, no studies have investigated blood gases following either long-acting buprenorphine preparation.The objective of the current study was to use a crossover design to evaluate the effects of a clinically applicable, single dose of subcutaneous BUP, BUP SR, or BUP ER on voluntary running-wheel activity, resting arterial blood gases, and antinociception according to a thermal withdrawal model in healthy adult rats. Administration of all formulations was hypothesized to produce quantifiable thermal analgesia, reduce voluntary running activity, and result in mild hypoventilation and arterial hypoxemia after injection in healthy adult rats. In addition, the effects were predicted to be of similar magnitude among BUP, BUP SR, and BUP ER but of shorter duration in the BUP group compared with the BUP SR and BUP ER groups.