Anti-nociception is selectively enhanced by parallel inhibition of multiple subtypes of monoamine transporters in rat models of persistent and neuropathic pain.
BACKGROUND
Neuropathic pain is characterised by hyperexcitability within nociceptive pathways that manifests behaviourally as allodynia and hyperalgesia and remains difficult to treat with standard analgesics. However, antidepressants have shown reasonable preclinical and clinical anti-nociceptive efficacy against signs and symptoms of neuropathic pain.


OBJECTIVE
To ascertain whether inhibition of serotonin (5-HT) and/or noradrenaline (NA) and/or dopamine (DA) re-uptake preferentially mediates superior anti-nociception in preclinical pain models.


METHODS
The 5-HT re-uptake inhibitor fluoxetine (3-30 mg/kg), the NA re-uptake inhibitor reboxetine (3-30 mg/kg), the dual 5-HT and NA re-uptake inhibitor venlafaxine (3-100 mg/kg) and the dual DA and NA re-uptake inhibitor bupropion (3-30 mg/kg) were tested after intraperitoneal administration in rat models of acute, persistent and neuropathic pain.


RESULTS
Reboxetine and venlafaxine dose-dependently attenuated second-phase flinching in the formalin test; fluoxetine attenuated flinching only at the highest dose tested, whereas bupropion was ineffective. In the chronic constriction injury (CCI) and spinal nerve ligation models of neuropathic pain, hindpaw mechanical allodynia was significantly attenuated by fluoxetine and particularly by bupropion. Reboxetine and venlafaxine were completely ineffective. In contrast, reboxetine and venlafaxine reversed thermal hyperalgesia in CCI rats, whereas bupropion and fluoxetine were either minimally effective or ineffective. Fluoxetine, reboxetine and venlafaxine transiently increased the tail-flick latency in uninjured animals. Anti-nociceptive doses of drugs had no effect on motor function.


CONCLUSIONS
Combined re-uptake inhibition of 5-HT and NA appears to confer a greater degree of anti-nociception in animal models of experimental pain than single mechanism of action inhibitors. The selective attenuation of mechanical allodynia by bupropion suggests that the additional re-uptake of DA may further augment 5-HT/NA re-uptake mediated anti-nociception after nerve injury.
Pedersen
Louise H
LH
Department of Pharmacology, NeuroSearch A/S, 93 Pederstrupvej, 2750, Ballerup, Denmark.
Nielsen
Alexander N
AN
Blackburn-Munro
Gordon
G
D000588:Amines / Q000627:therapeutic use; D000700:Analgesics / Q000627:therapeutic use; D000704:Analysis of Variance; D000818:Animals; D000928:Antidepressive Agents / Q000627:therapeutic use*; D001522:Behavior, Animal / Q000187:drug effects; D016642:Bupropion / Q000627:therapeutic use; D003250:Constriction; D003509:Cyclohexanecarboxylic Acids / Q000627:therapeutic use; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005473:Fluoxetine / Q000627:therapeutic use; D000077206:Gabapentin; D008297:Male; D009025:Morpholines / Q000627:therapeutic use; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D014179:Neurotransmitter Uptake Inhibitors / Q000145:classification / Q000627:therapeutic use*; D010146:Pain / Q000145:classification / Q000188:drug therapy* / Q000209:etiology; D010147:Pain Measurement / Q000379:methods; D017288:Pain Threshold / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077593:Reboxetine; D045442:Rotarod Performance Test / Q000379:methods; D013119:Spinal Cord Injuries / Q000150:complications / Q000188:drug therapy; D050493:Vesicular Monoamine Transport Proteins / Q000037:antagonists & inhibitors*; D005680:gamma-Aminobutyric Acid / Q000627:therapeutic use
D000588:Amines; D000700:Analgesics; D000928:Antidepressive Agents; D003509:Cyclohexanecarboxylic Acids; D009025:Morpholines; D014179:Neurotransmitter Uptake Inhibitors; D050493:Vesicular Monoamine Transport Proteins; D005473:Fluoxetine; D016642:Bupropion; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin; D000077593:Reboxetine