Abstract
Introduction. Recently a prolonged release depot formulation of buprenorphine, Buvidal®, has been approved in Europe for the treatment of opioid dependence [1]. Melichar and colleagues have shown that clinically, this prolonged release depot buprenorphine (DEP-BUP) , provided as weekly/monthly depot injection, provides reduction in craving and anxiety symptoms in opioid-dependent patients [2]. Buprenorphine is a partial mu opioid receptor (MOP) agonist and a kappa opioid receptor (KOP) antagonist, and at higher concentrations is an antagonist at the delta opioid receptor and a partial agonist at the opioid receptor like 1 (ORL1) receptor [3]. We have investigated the duration of KOP antagonism following DEP-BUP administration or acute buprenorphine administration in rats.
Methods. Adult male and female Sprague-Dawley rats (8-11 weeks) were used. The warm water (50 ℃) tail withdrawal assay was used to assess the response to the KOP agonist spiradoline (20 mg/kg, subcutaneously). Rats were habituated to handling and randomly assigned to treatment groups. All rats were injected with the MOP antagonist clocinnamox (CCAM, 4mg/kg in 6.7% ethanol/saline, intraperitoneally) on day 0. Twenty-four hours later, baseline latency was tested and rats were injected with saline (0.9% w/v), buprenorphine 0.45 mg/kg, DEP-BUP (once weekly preparation 32 mg/0.64 ml supplied by Camurus, diluted 1:1 with vehicle, administered 0.4 l/g body weight to produce a depot that achieves blood levels equivalent to 0.45mg/kg acute administration) or placebo vehicle (all treatments subcutaneously). The response to spiradoline was assessed 1h and 20h later. Antinociception was calculated as percentage maximum possible effect (% MPE) = (test latency-control latency)/(20s-control latency) x 100. Values reported are mean +/- sem (n=5 per group) and the effect of time on the treatment response determined using paired t-tests.
Results. Acute administration of buprenorphine (0.45 mg/kg) significantly blocked the antinociceptive effects of spiradoline after 1h, but not 20h, in both male and female rats (Table 1). For DEP-BUP, the response to spiradoline was attenuated at both 1h and 20h.
Table 1. Antinociceptive response to spiradoline (20 mg/kg) in rats pre-treated with acute buprenorphine (BUP) or saline and prolonged release depot formulation of buprenorphine (DEP-BUP) or vehicle.
*P<0.025 versus 1h timepoint within treatment group
Conclusions. DEP-BUP displayed extended KOP antagonist activity against spiradoline in both male and female rats. We are investigating whether there is prolonged KOP antagonism at longer treatment durations. KOP antagonism has been proposed as an anxiolytic therapeutic strategy [3] and further studies will be conducted to assess the behavioural impact of DEP-BUP in rodents.
Methods. Adult male and female Sprague-Dawley rats (8-11 weeks) were used. The warm water (50 ℃) tail withdrawal assay was used to assess the response to the KOP agonist spiradoline (20 mg/kg, subcutaneously). Rats were habituated to handling and randomly assigned to treatment groups. All rats were injected with the MOP antagonist clocinnamox (CCAM, 4mg/kg in 6.7% ethanol/saline, intraperitoneally) on day 0. Twenty-four hours later, baseline latency was tested and rats were injected with saline (0.9% w/v), buprenorphine 0.45 mg/kg, DEP-BUP (once weekly preparation 32 mg/0.64 ml supplied by Camurus, diluted 1:1 with vehicle, administered 0.4 l/g body weight to produce a depot that achieves blood levels equivalent to 0.45mg/kg acute administration) or placebo vehicle (all treatments subcutaneously). The response to spiradoline was assessed 1h and 20h later. Antinociception was calculated as percentage maximum possible effect (% MPE) = (test latency-control latency)/(20s-control latency) x 100. Values reported are mean +/- sem (n=5 per group) and the effect of time on the treatment response determined using paired t-tests.
Results. Acute administration of buprenorphine (0.45 mg/kg) significantly blocked the antinociceptive effects of spiradoline after 1h, but not 20h, in both male and female rats (Table 1). For DEP-BUP, the response to spiradoline was attenuated at both 1h and 20h.
Table 1. Antinociceptive response to spiradoline (20 mg/kg) in rats pre-treated with acute buprenorphine (BUP) or saline and prolonged release depot formulation of buprenorphine (DEP-BUP) or vehicle.
*P<0.025 versus 1h timepoint within treatment group
Conclusions. DEP-BUP displayed extended KOP antagonist activity against spiradoline in both male and female rats. We are investigating whether there is prolonged KOP antagonism at longer treatment durations. KOP antagonism has been proposed as an anxiolytic therapeutic strategy [3] and further studies will be conducted to assess the behavioural impact of DEP-BUP in rodents.
Original language | English |
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Journal | British Journal of Pharmacology |
Volume | 180 |
Issue number | 4 |
Publication status | Published - 6 Sept 2022 |