Current Opinion in Investigational Drugs

44 Current Opinion in Investigational Drugs 2006 Vol 7 No 1
both an intensity- and duration-dependent manner [10•]. Thus,
the sustained, intense nociception associated with adjuvant
arthritis may have sufficiently inhibited opioid analgesia
tolerance development for morphine analgesia to have
remained significant, at least over the 2-week period. Agents
exemplifying other central mechanisms of analgesia (eg, the 5-
HT and noradrenaline re-uptake inhibitor imipramine (2.5
mg/day), the excitatory amino acid antagonist ketamine (20
mg/day), and the anticonvulsant gabapentin (10 mg/day))
were inactive (Table 3). Similar to tonic nociceptive pain, the
data suggest that high-efficacy 5-HT1A receptor activation
produces an analgesia with chronic nociceptive pain that is
rivaled only, if at all, by morphine-like opioids.
Chronic neuropathic pain
In a model of peripheral neuropathic pain, rats undergo a
unilateral chronic constriction injury of the common sciatic
nerve and demonstrate a lowered threshold for von Frey
filament stimulation to induce paw withdrawal [33]. A 2-week
infusion of morphine, ketamine or imipramine produced a
slight, non-significant increase of the ipsilateral reduced
threshold in saline-treated rats (17 g), while gabapentin exerted
a significant effect (Table 3). F-13640 produced a larger, highly
significant increase, suggesting robust efficacy in this model
[15•]. This effect on ipsilateral threshold was behaviorally
specific, in that F-13640 did not modify the contralateral
threshold in saline-treated rats (69 g).
In a model of central neuropathic pain, rats received a
photochemical, ischemic injury of spinal cord dorsal segments
L3 to L5 and developed allodynic responses to cutaneous
stimulations such as von Frey filament application, a gentle
brush or a cold spray [34]. Interestingly, and as with sciatic
nerve constriction, subcutaneously infused morphine,
ketamine, imipramine and gabapentin increased the von Frey
threshold to some extent, although not significantly so; these
agents also exerted no significant effect in response to a gentle
brush or a cold spray (Table 3). In contrast, F-13640 robustly
inhibited all three responses [15•]. The effects of F-13640 grew
in the course of the 2-week treatment period, demonstrating
inverse analgesic tolerance.
The acute injection of F-13640, as well as that of morphine,
can counteract allodynic responses to von Frey filament
stimulation in rats sustaining a chronic constriction injury of
the infra-orbital nerve (IoN-CCI), a model of trigeminal
neuropathic pain [35]. The effects of F-13640 in this model
are again behaviorally specific [36]. In these rats, morphine
infusion initially produces a robust, significant analgesia to
which complete tolerance develops after 2 weeks; the effects
of F-13640 increased rather than declined during the 2-week
period, again demonstrating inverse tolerance [37•,38,39,40•].
Collectively, these data suggest that high-efficacy 5-HT1A
receptor activation may produce exceptionally powerful and
sustained, 'symptomatic' analgesia with chronic neuropathic
pain of peripheral or central origin.
Pre-emptive and curative-like analgesia
Much as opioids induce a hyperalgesia and tolerance that
may outlast µ-opioid receptor activation for a long time (eg,
a year [10•,41]), the signal-transduction concept suggests
that a neuropharmacological manipulation that generates
the inverse of opioid actions should induce analgesia (and
continue to demonstrate inverse tolerance) long after its
implementation has been discontinued.
Rats were infused with 0.63 mg/day of F-13640 for 8 weeks
starting 24 h before the spinal cord injury described
previously; with all three cutaneous stimulations the
treatment effect persisted unabated for 2 months following
discontinuation of treatment [42]. These data, together with
the consideration that F-13640 is effective in neuropathic
pain regardless of its peripheral or central origin, suggest
that high-efficacy 5-HT1A receptor activation may
powerfully 'pre-empt' pain ensuing from neuronal damage,
such as that resulting from surgical nerve injury or diabetes.
To explore this suggestion, rats having sustained spinal cord
injury and having fully developed allodynia were then
infused with F-13640 (0.63 mg/day) for 56 days. The
treatment increasingly alleviated and eventually normalized
the allodynic responses, thereby demonstrating inverse
tolerance. More importantly, during the 70-day period that
ensued, the effects of F-13640 persisted, demonstrating an
unprecedented 'curative-like' action on allodynic pain [40•].
It remains to be determined whether these pre-emptive and
curative-like actions are mediated by the neuron-protective
and astroglial reaction-inhibitory effects that 5-HT1A
agonists may produce in ischemic brain tissue [43].
Although it might be of interest to similarly examine the
potential pre-emptive and curative-like actions of morphine,
ketamine, imipramine and gabapentin, the absence of
significant symptomatic effects with these agents in the
spinal cord injury model has prevented the research group
from doing so. Indeed, any such pre-emptive actions
reported so far have concerned pain parameters that
respond in a symptomatic manner to the agents being
considered [44,45]. Prominent among these agents are
opioids, and the largest symptomatic effects observed to
date with continuous, 2-week infusion of any comparable
analgesic in any model of neuropathic pain were obtained
with 5 mg/day of morphine in the IoN-CCI model [37•,38].
As indicated, soon after the initiation of morphine infusion,
a robust analgesia occurs in this model, to which tolerance
develops within 2 weeks. At that stage, discontinuation of
morphine infusion does not afford analgesia, and in fact
causes hyperallodynia [53].
Tolerability
Although the data discussed previously allow assessment of
the comparative therapeutic potential of F-13640 relative to
currently available treatments to a considerable extent, the
evidence available so far offers only little in the way of an
evaluation of the relative tolerability of the compound.
Regarding the opioids, however, one issue stands out; it is
now recognized that the chronic use of opioids induces an
analgesic tolerance that not only limits, or dissipates their
therapeutic usefulness, but is also accompanied by
hyperalgesia and opioid-induced pain [10•,13,14]. In
addition to the well-known side effects of opioids, this druginduced
pain may become 'excruciating', thus severely