Using eight rhesus monkeys, Ko et al. evaluated time course and dose dependency of scratching responses and antinociception after intrathecal administration of morphine. One monkey had been previously exposed to short-term opioids, whereas three had long-term exposure before the study. However, none of the monkeys received any opioids for 1 month before the present study.
Initially, the monkeys were anesthetized with ketamine, and spinal needles were inserted into the subarachnoid interspace between L4/L5 or L5/L6 lumbar vertebrae. A 1-ml saline solution of morphine was slowly infused through the spinal needle within 30 s, and monkeys were then returned to their home cages. Experimental sessions took place a maximum of three to four times per month in each monkey and were spaced 8–10 days apart to prevent possible development of opioid tolerance.
The first four monkeys were used only to study intrathecal morphine-induced scratching responses and to evaluate the efficacy of intravenous nalmefene in attenuating scratching responses. Monkeys were videotaped 15 min/h for 6 h after intrathecal morphine administration. Scratching responses, defined as 1-s episodes of scraping contact of the forepaw or hind paw on the skin surface, were counted by independent observers blinded to experimental conditions. The researchers found that low to medium doses of intrathecal morphine (1–32 μg) induced scratching in a dose-dependent fashion. Peak effects were observed at 1–2 h after intrathecal injection, and scratching lasted for at least 6 h. The team observed that monkeys had different susceptibilities to intrathecal morphine–induced scratching, with 32 μg intrathecal morphine inducing profound scratching responses in two monkeys but not in the others. Statistical analysis indicated that intrathecal morphine from low doses (1 or 3.2 μg) to high doses (320 μg) significantly evoked scratching responses compared with saline injections and reached a plateau for most monkeys at higher doses in the range of 100–320 μg.
The second group of four monkeys had been previously trained in the warm-water tail-withdrawal procedure for assessing antinociception and were therefore used for both scratching responses and antinociceptive studies. The effects of intrathecal morphine were studied during six 1-h test sessions by giving different doses randomly in a single dosing procedure. These monkeys displayed a consistent profile in warm-water tail-withdrawal responses. Medium to high doses of intrathecal morphine (10–320 μg) dose-dependently produced thermal antinociception in 50°C water. However, the researchers admit that this behavioral measurement may have been influenced by ketamine administered before the intrathecal injection.
Nalmefene, an opioid antagonist, attenuated maximum scratching responses when given intravenously (10–32 μg/kg). Pretreatment with nalmefene produced 10-fold rightward shifts of the intrathecal morphine dose–response curve for both scratching and antinociception.
This is the first primate mode of itching produced by intrathecal opioids and may prove useful for both exploring the mechanisms and treatment of this bothersome side effect of a valuable clinical technique.