Intranasal Opioid Administration in Rhesus Monkeys: PET Imaging and Antinociception

Abstract

The goal of this study was to evaluate the effects of intranasally administered opioids in rhesus monkeys using the tail-withdrawal assay, and to correlate these effects with measures of receptor occupancy using positron emission tomography (PET) imaging. Initial experiments characterized the antinociceptive effects of intranasal (IN) fentanyl and buprenorphine relative to intramuscular (IM) injection. Fentanyl (0.010-0.032 mg/kg) and buprenorphine (0.1-1.0 mg/kg) produced dose-dependent increases in tail-withdrawal latency that did not differ between routes of delivery. The second experiment compared the ability of IN and intravenous (IV) naloxone (NLX) to block the antinociceptive effects IV fentanyl, and to measure receptor occupancy at equipotent doses of NLX using PET imaging. IN and IV NLX (0.0032-0.032 mg/kg) produced dose-dependent decreases in fentanyl-induced antinociception. Again, there was no difference observed in overall potency between routes. PET imaging showed that IV and IN NLX produced similar decreases in receptor occupancy as measured by [¹¹C]carfentanil blocking, although there was a trend for IV NLX to produce marginally greater occupancy changes. This study validated the first procedures to evaluate the IN effects of opioids in rhesus monkeys.

Fig. 1.

The effect of fentanyl IN (A) and IM (B) on mean (±S.E.M.) tail-withdrawal latency in 50°C water plotted as a function of dose and time in rhesus monkeys (n = 3). Abscissae: Time in minutes (min). Ordinates: Tail-withdrawal latency presented as MPE. (C) Averaged (± S.E.M.) peak measurement of tail-withdrawal latency taken from the time-course data for fentanyl administered IN (black bars) and IM (gray bars). Abscissae: Saline or fentanyl dose, 0.010, 0.018 and 0.032 mg/kg. Tail-withdrawal latency presented as MPE. Significant differences between fentanyl and saline are indicated by, *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001. Significant differences between routes of administration are indicated by ^#P ≤ 0.05.

Fig. 2.

Mean (±S.E.M.) tail-withdrawal latency from 50°C water expressed as MPE and plotted as a function of dose and time for IN (A) and IM (B) buprenorphine administration in rhesus monkeys (n = 3). Abscissae: Time in minutes (min). Ordinates: Tail-withdrawal presented as MPE. (C) Averaged (±S.E.M.) peak measurement of tail-withdrawal latency taken from the time-course data for buprenorphine administered IN (black bars) and IM (gray bars). Vehicle and buprenorphine doses, 0.1, 0.32, and 1.0 mg/kg. Tail-withdrawal latency presented as MPE. Significant differences between buprenorphine and saline are indicated by: *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001.

Fig. 3.

Time-course data for the effects of NLX (0.0032–0.032 mg/kg) administered IN (A) and IV (B) to block fentanyl-induced increases in tail-withdrawal latency in rhesus monkeys (n = 3). Data are presented as the mean (±S.E.M.) maximum percent effect and plotted as a function of time. Abscissae: Time in minutes (min). Ordinates: Tail-withdrawal latency presented as MPE. (C) Mean (±SEM) tail-withdrawal latency from 50°C water averaged across the 90-minute session produced with IV fentanyl alone and in the presence of IN and IV NLX (0.0032–0.032 mg/kg). Abscissae: IV fentanyl (0.018 mg/kg) alone (F) and doses of naloxone. Ordinates: Tail-withdrawal latency presented as MPE. Significant differences between fentanyl alone and different doses of naloxone are indicated by: *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001

Fig. 4.

Brain tissue time-radioactivity curves for selected brain regions. TACs from [¹¹C]CFN alone (top panel) and in the presence of NLX 0.032 mg/kg delivered IN (middle panel) and IV (bottom panel). Abscissae: Time in minutes (min). Ordinates: Measures of radioactivity in nano-Curies per cubic centimeter per milli-Curies injected (nCi/cc/inj).

Fig. 5.

Percent receptor availability in selected brain regions following IN and IV NLX (0.032 mg/kg). RO was estimated as the ratio of DVR values obtained from PET images with [¹¹C]CFN alone relative to the DVRs calculated after NLX blocking experiments.

Fig. 6.

Representative coronal microPET images of [¹¹C]CFN alone (left) and following blocking studies with IN (middle), and IV (right) NLX (0.032 mg/kg). Summed images 0–60 minutes following IV injection of the radiotracer.