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The antipsychotic drug, fluphenazine, effectively reverses mechanical allodynia in rat models of neuropathic pain

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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 allodynia 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 mechanical 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.

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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

INa :

sodium current

i.p.:

intraperitoneal

%MPE:

percent maximum possible effect

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Authors and Affiliations

  1. Department of Neurobiology, Schering-Plough Research Institute, K-15-2-2600, 2015 Galloping Hill Road, Kenilworth, NJ, 07033, USA

    Xiao-Wei Dong, Yuping Jia, Sherry X. Lu, Xiaoping Zhou, Mary Cohen-Williams, Robert Hodgson, Huiqing Li & Tony Priestley

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  1. Xiao-Wei Dong
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  2. Yuping Jia
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  3. Sherry X. Lu
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  4. Xiaoping Zhou
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  6. Robert Hodgson
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  7. Huiqing Li
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  8. Tony Priestley
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Correspondence to Xiao-Wei Dong.

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Supplementary Fig. 1

Inhibition of sodium currents in DRG neurons by fluphenazine. (a), current-voltage relationship for whole-cell sodium currents, in medium sized DRG neurons, obtained in the absence of fluphenazine. Whole-cell currents were evoked using a series of depolarizing steps from a membrane potential of −120 mV, in 10-mV increments, to a final command potential of 50 mV (the voltage protocol shown in the insert). Peak current was evoked at −10 mV. Data are presented as the fraction of peak current (mean ± SEM, n = 7). (b), Effect of fluphenazine on total sodium currents in DRG neurons. The superimposed traces are representative peak sodium currents before and during bath application of 10 μM and 30 μM fluphenazine. Fluphenazine caused a dose-dependent inhibition of total sodium currents. (c), Effect of fluphenazine on TTXr sodium currents. The largest current represents total sodium current evoked at −10 mV. TTX (300 nM) was then added to the perfusate resulting, in this case, a ∼60% reduction in current amplitude (black line). This TTXr current was reduced by ∼30% following the perfusion of fluphenazine (10 μM). (d), Fluphenazine concentration-response curves for tonic block of total (○)(n = 5) and TTXr (•) (n = 5) currents recorded from DRG neurons. Fluphenazine showed slightly higher (∼4-fold) potency on TTXs currents compared with TTXr current. (GIF 67.2 KB)

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Dong, XW., Jia, Y., Lu, S.X. et al. The antipsychotic drug, fluphenazine, effectively reverses mechanical allodynia in rat models of neuropathic pain. Psychopharmacology 195, 559–568 (2008). https://doi.org/10.1007/s00213-007-0942-5

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  • DOI: https://doi.org/10.1007/s00213-007-0942-5

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