ORIGINAL INVESTIGATION
The antipsychotic drug, fluphenazine, effectively reverses
mechanical allodynia in rat models of neuropathic pain
Xiao-Wei Dong
&
Yuping Jia
&
Sherry X. Lu
&
Xiaoping Zhou
&
Mary Cohen-Williams
&
Robert Hodgson
&
Huiqing Li
&
Tony Priestley
Received: 19 October 2006 / Accepted: 5 September 2007 / Published online: 23 September 2007
#
Springer-Verlag 2007
Abstract
Rationale Fluphenazine is a potent antipsychotic drug used
to treat schizophrenia and other psychotic symptoms. Its
clinical benefit is mainly mediated by the antagonism of
dopamine D2 receptors. We have recently discovered,
however, that fluphenazine is also a potent sodium channel
blocker, a property that may offer additional therapeutical
indications, including analgesia.
Objectives The present study sought to determine the
analgesic effect of fluphenazine on neuropathic pain in
animal models.
Methods The effect of fluphenazine on mechanical allody-
nia was assessed in three animal neuropathic pain models,
including spinal nerve ligation, chronic constriction nerve
injury (CCI), and sural-spared sciatic nerve injury models.
Results Systemic fluphenazine effectively attenuated me-
chanical allodynia in all three rat neuropathic pain models
at doses (0.03–0.3 mg/kg) that approximate those used in
rodent models of psychosis. In parallel with its in vivo
antiallodynic effect, fluphenazine (3–30 μM) effectively
suppressed the ectopic discharges in injured afferent fibers
without affecting the propagation of action potentials
evoked by electrical nerve stimulation in an ex vivo dorsal
root ganglia (DRG)-nerve preparation excised from CCI
rats. Furthermore, similar concentrations of fluphenazine
significantly blocked sodium channels in DRG neurons.
Conclusions The inhibitory action of fluphenazine on
ectopic afferent discharges may be due to its ability to
block voltage-gated sodium channels, and this may also
provide a mechanistic basis for the drug’s antiallodynic
effect in animal models of neuropathic pain. In summary,
our study demonstrates that the classic antipsychotic drug
fluphenazine has antiallodynic properties in multiple rodent
models of nerve injury-induced neuropathic pain.
Keywords Neuropathic pain
.
Allodynia
.
Sodium channel
.
Fluphenazine
.
Ectopic discharges
.
Dorsal root ganglia
Abbreviations
SNL spinal nerve ligation
CCI chronic constriction nerve injury
SNI sural-spared sciatic nerve injury
TTXs tetrodotoxin-sensitive
TTXr tetrodotoxin-resistant
DRG dorsal root ganglia
L6 (4, 5) lumbar 6 (4, 5)
PWT paw withdrawal threshold
ACSF artificial cerebrospinal fluid
DMEM Dulbecco’s modified Eagle’s medium
NGF nerve growth factor
I
Na
sodium current
i.p. intraperitoneal
%MPE percent maximum possible effect
Introduction
Fluphenazine (Prolixin®) is a potent phenothiazine antipsy-
chotic agent that was approved for clinical use in the late
1950s (Taylor 1959) and quickly became established as an
Psychopharmacology (2008) 195:559–568
DOI 10.1007/s00213-007-0942-5
Electronic supplementary material The online version of this article
(doi:10.1007/s00213-007-0942-5) contains supplementary material,
which is available to authorized users.
X.-W. Dong (*)
:
Y. Jia
:
S. X. Lu
:
X. Zhou
:
M. Cohen-Williams
:
R. Hodgson
:
H. Li
:
T. Priestley
Department of Neurobiology, Schering-Plough Research Institute,
K-15-2-2600, 2015 Galloping Hill Road,
Kenilworth, NJ 07033, USA
e-mail: zoe.dong@spcorp.com