Amitriptyline, a non-selective
noradrenaline (NA) and
5-hydroxytryptamine (5-HT) reuptake inhibitor, has recently been demonstrated to produce a peripheral antinociceptive action in an inflammatory (
formalin test) and a
neuropathic pain model (spinal nerve
ligation). In the present study, we determined whether
desipramine, a selective NA reuptake inhibitor, and
fluoxetine, a selective
5-HT reuptake inhibitor, could produce peripheral antinociceptive actions in these same tests. Effects on paw volume also were determined. In the 2.5%
formalin test,
desipramine and
fluoxetine 10-300 nmol produced a dose-related reduction in phase 2 (16-60 min) flinching and biting/licking behaviours when coadministered with the
formalin. Phase 1 flinch behaviours (0-12 min) were significantly reduced at the highest dose. These actions are peripherally mediated, as they were not seen when
desipramine or
fluoxetine (100, 300 nmol) were injected into the contralateral hindpaw. The peripheral action of
desipramine and
fluoxetine was not altered by coadministration of
caffeine 1500 nmol. In the spinal nerve
ligation model,
desipramine 100 nmol, but not
fluoxetine 100 nmol, produced a peripheral anti-hyperalgesic action in the hindpaw corresponding to the ligated side when thresholds were determined using a thermal paw stimulator. In paw volume experiments,
desipramine, at doses which are maximally effective in behavioural tests, produced only a slight increase in paw volume, but
fluoxetine (10-300 nmol) produced a robust and sustained dose-related increase in paw volume.
Amitriptyline also produced minimal effects on paw volume. When coinjected with
formalin, no agent significantly altered the degree of paw swelling produced by
formalin. The increase in paw volume produced by
fluoxetine was inhibited by
ketanserin (5-HT2 receptor antagonist),
mepyramine (
histamine H1 receptor antagonist) and
phentolamine (
alpha-adrenergic receptor antagonist), but not by the other selective
5-HT receptor antagonists tested or
caffeine. The pronounced peripheral
pain alleviating actions in the absence of marked changes in paw volume produced by
desipramine and
amitriptyline, but not
fluoxetine, in the
formalin test and the spinal nerve
ligation model suggest that these agents could be developed as cream or gel formulations to recruit a peripheral antinociceptive action in inflammatory and
neuropathic pain states. Such a formulation might permit the attainment of higher and more efficacious concentrations in the region of the sensory nerve terminal, with limited systemic side effects.