Current Opinion in Investigational Drugs

40 Current Opinion in Investigational Drugs 2006 Vol 7 No 1
5-HT1A receptor activation: New molecular and neuroadaptive mechanisms
of pain relief
Francis C Colpaert
Address
Institut de Recherche Pierre Fabre
3 rue des Satellites
BP 94244
31432 Toulouse Cedex 4
France
Email: francis.colpaert@pierre-fabre.com
Current Opinion in Investigational Drugs 2006 7(1):40-47
© The Thomson Corporation ISSN 1472-4472
Guided by an understanding of signal transduction in painprocessing
systems, high-efficacy 5-hydroxytryptamine (5-
HT)1A receptor activation, by means of F-13640, has been
discovered as a new molecular mechanism of pain relief in
laboratory animals, inducing two neuroadaptive phenomena.
Firstly, this activation cooperates with nociceptive stimulation,
paradoxically causing analgesia, and secondly, inverse
tolerance develops so that the resulting analgesia grows rather
than decays. As an apparent result of these novel
neuroadaptive mechanisms, F-13640 exerts an analgesic action
in rat models of acute, tonic and chronic nociceptive pain that
is rivaled only by large doses of high-efficacy µ-opioid receptor
agonists. In models of neuropathic allodynia of peripheral or
central origin, chronic F-13640 administration causes an
analgesia that surpasses that observed with morphine or other
agents exemplifying other central nervous system drug
mechanisms of pain relief (eg, ketamine, imipramine and
gabapentin). Indeed, F-13640 produces long-lasting, preemptive
and, most remarkably, curative-like actions in
neuropathic allodynia. Although awaiting proof-of-concept
evidence in humans, high-efficacy 5-HT1A receptor activation
may uniquely challenge the opioids for pain therapy.
Keywords 5-HT1A receptors, analgesia, neuropathic pain,
nociceptive pain, opioids, tolerance
Introduction
Neuroanatomical and physiological studies have long
implicated serotonin (5-hydroxytryptamine; 5-HT) in the
central nervous system (CNS) control of pain (eg, descending
inhibition) [1], and while a host of 5-HT receptors are known to
mediate the cellular actions of serotonin [2], the 5-HT1A
serotonin receptor subtype has not traditionally been
considered as a molecular target for pain therapy [3-8].
However, it will be argued here that high-efficacy activation of
CNS 5-HT1A receptors may perhaps now begin to challenge the
opioids as an option for the treatment of pain, although the
latter have been the mainstay treatment of pain for over
thousands of years. Somewhat ironically, this stark
development results from studies into opioid tolerance in the
1970s, and from a well-accepted concept that attempted to
account for tolerance to opioid analgesia.
Signal transduction in pain-processing systems
The concept accounting for opioid analgesia tolerance specifies
that any input to pain-processing systems causes not a single
effect, but dual effects that are bidirectional, or opposite, in sign
[9,10•,11,12]. Thus, morphine causes not only analgesia as a
'first-order' effect, but also a 'second-order' hyperalgesia that
outlasts opioid receptor activation for some time. The first-order
analgesia results directly from receptor activation, but the
second-order effect is an indirect consequence of this analgesia
and follows in time. Upon chronic opioid exposure, the secondorder
pain, or sensitization to nociceptive input, grows and
counteracts the first-order analgesia. Thus, opioid tolerance is
due, paradoxically, to opioid pain [10•,13,14].
Intriguingly, the concept of high-efficacy activation of 5-HT1A
receptors as an option for the treatment of pain suggested that a
mechanism wholly different from opioid receptor activation
could possibly exist, whereby analgesia could be produced.
Indeed, according to this concept, the stimulation of peripheral
nociceptors would initially produce pain as a first-order effect,
but also hypoalgesia as a second-order effect; with chronicity,
this second-order hypoalgesia should grow, counteract the firstorder
pain and, remarkably, develop into an increasingly
powerful analgesia (ie, inverse tolerance). Of equal importance,
according to the concept, is that one nociceptive stimulation
should cooperate with another, concomitant stimulation of
nociceptors to paradoxically induce second-order hypoalgesia
[4,9]. The potential of such an intervention is considerable; it
would be most effective in the treatment of severe pain and
would resolve inaccessible, opioid-resistant, chronic pains.
Thus, since the 1970s, researchers currently at Pierre Fabre SA
have employed an increasing array of neuropharmacological
tools in an attempt to identify a mammalian protein and a
molecular action by which the central effects of peripheral
nociceptive stimulation can be mimicked. This protein should
initiate the neuroadaptive mechanisms of inverse tolerance and
nociceptor cooperation, and its effects should constitute the
opposite of those of opioids. 5-HT1A receptor activation has
now been identified as the neuropharmacological intervention
whereby those neuroadaptive and therapeutic objectives can
possibly be achieved [15•].
F-13640
F-13640 (Pierre Fabre SA; Figure 1) is a newly synthesized
methylamino-pyridine that has nanomolar and selective affinity
for both rat and human G-protein-coupled 5-HT1A receptors; at
1000-fold higher concentrations the compound does not interact
with many other neurotransmitter receptors, uptake sites, ion
channels and enzymes. Importantly, F-13640 has strong activity
at 5-HT1A receptors and stimulates [ 35S]GTPγS binding by a
magnitude far greater than that observed with the 5-HT1A
agonists buspirone and 8-hydroxy-2-di-n-propylamino-tetralin
(8-OH-DPAT), and more recently identified selective 5-HT1A
agonists [15•,16,17]. This combination of potency, selectivity
and high efficacy can also be observed in vivo; after
intraperitoneal injection in rat, F-13640 readily penetrates the
brain [18], inhibits spinal-cord-wide dynamic neuron and
single motor unit responses to nociceptive electrical
stimulation [19], and exerts analgesia from (ED50) doses of
0.029 mg/kg upwards [20•]. Its effects are consistently