Marijuana and the Cannabinoids

308 Musty
was measured using the radiant tail flick test, Von Frey filaments, and the hot-plate
test, respectively. Tactile allodynia but not thermal hyperalgesia was found. WIN 55-
212-2a, a cannabinoid receptor agonist that acts in the CNS but is not inhibited by the
CB 1 antagonist AM 251, produced a dose-dependent decrease in allodynia at doses of
1, 5, and 10 mg/kg.
Ibrahim et al. (17) tested the effects of AM 1241 (a selective CB 2 receptor agonist)
on experimental neuropathic pain in rats. Tactile hypersensitivity and thermal
hypersensitivity were induced by ligation of L5 and L6 spinal nerves. AM 1241 dosedependently
reversed hypersensitivity. When tested in CB 1 knockout mice using the
same ligation procedure, AM 1241 was effective in reducing pain sensitivity, suggesting
that this peripherally active agonist blocks neuropathic pain. The authors suggest
that CB 2 receptor agonists, devoid of CNS activity, are predicted to be effective without
the CNS side effects of centrally acting cannabinoid agonists.
Johanek and Simone (18) examined whether or not cannabinoids attenuated
hyperalgesia produced by a mild heat injury to the glabrous hind paw and if the
antihyperalgesia was receptor-mediated. Mild heat injury (55°C for 30 seconds) to
one hind paw was given to anesthetized rats. Fifteen minutes after injury, decreased
withdrawal latency to radiant heat and increased withdrawal frequency to a von Frey
monofilament (200 mN force) delivered to the injured hindpaw was observed.
Intraplantar injection of vehicle or the agonist WIN 55,212-2 (1, 10, or 30 µg in 100 µL)
decreased heat and and mechanical hyperalgesia in a dose-dependent fashion, whereas
the inactive enantiomer WIN 55,212-3 did not. The CB 1 receptor antagonist AM 251
(30 µg) co-injected with WIN 55,212-2 (30 µg) decreased the antihyperalgesic effects
of WIN 55,212-2,.and CB 2 receptor antagonist AM 630 (30 µg) co-injected with WIN
55,212-2 decreased the antihyperalgesic effects of the agonist. Injection of WIN 55,212-
2 into the contralateral paw did not change heat-injury-induced hyperalgesia. These
results suggest that antihyperalgesia was mediated by peripheral mechanisms. The
authors conclude, like Ibrahim (17), that this reduction of hyperanalgesia may be
peripheral.
Nackley et al. (19) examined the effects of CB 2 -selective cannabinoid agonist
AM1241 on activity in spinal wide dynamic range neurons by transcutaneous electrical
stimulation urethane-anesthetized rats during either carrageenan inflammation or
not. Intravenous administration decreased activity in wide dynamic range neurons
induced by stimulation. This effect was blocked by the CB 2 antagonist SR144528 but
not by the CB 1 antagonist SR141716A. In addition, activity of nonnociceptive neurons
recorded in the lumbar dorsal horn was not affected by AM1241.
In a recent report, Chichewizc and Welch (20) found that ∆ 9 -THC (20 mg/kg)
and morphine (20 mg/kg) induced analgesia in both vehicle-treated and morphinetolerant
mice. In both groups analgesia was equally effective, “indicating that analgesia
produced by the combination is not hampered by existing morphine treatment (no
cross tolerance to the combination).” Mice were tested with ∆ 9 -THC (20 mg/kg) and
morphine (20 mg/kg) twice daily for 6.5 days and tested for tolerance, and on day 8,
∆ 9 -THC tolerance was observed, but morphine tolerance did not occur. These results
suggest that low-dose combinations of ∆ 9 -THC and morphine might prevent morphine
tolerance. The authors conclude that combinations of these drugs may be useful in
chronic pain patients over morphine administration alone.