Role of serotonin 5-HT1A and opioid receptors in the antiallodynic effect of tramadol in the chronic constriction injury model of neuropathic pain in rats.
BACKGROUND
Tramadol (1RS, 2RS)-2-[(dimethylamino)-methyl]-1-(3-methoxyphenyl)-cyclohexanol) is an atypical centrally acting analgesic agent with weak opioid receptor affinity that, like some antidepressants, enhances the extraneuronal concentrations of the monoamine neurotransmitters, noradrenaline and serotonin, by interfering with their re-uptake and release mechanisms.


OBJECTIVE
The present study was undertaken to evaluate the potential role of 5-HT(1A) receptors and opioids receptors in the analgesic effect of tramadol in neuropathic pain. With this aim, the effect of either a selective 5-HT(1A) receptor antagonist (WAY-100635, N-2-[4-(2-methoxyphenyl-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexane carboxamide) or a selective 5-HT(1A) receptor agonist (8-OH-DPAT, 8-hydroxy-2-(di-n-propylamine) tetralin hydrobromide) or an opioid receptor antagonist (naloxone; naloxone hydrochloride dihydrate) was investigated in combination with tramadol by means of the cold-plate test in the chronic constriction injury model in rats.


RESULTS
The results showed that WAY-100635 (0.8 mg/kg) significantly enhanced the antiallodynic effect of non-effective doses of tramadol (5-10 mg/kg). In contrast, 8-OH-DPAT (0.5 mg/kg) counteracted the antiallodynic effect of an effective dose of tramadol (22 mg/kg). Naloxone (0.5 mg/kg) partially counteracted the antiallodynic effect of tramadol (22 mg/kg).


CONCLUSIONS
These findings suggest the involvement of opioid and 5-HT(1A) receptors in the antinociceptive effect of tramadol and support the idea that the combination of tramadol with compounds having 5-HT(1A) antagonist properties could be a new strategy to improve tramadol-induced analgesia in neuropathic pain.
Berrocoso
Esther
E
Pharmacology and Neuroscience Research Group, Department of Neuroscience (Pharmacology and Psychiatry), School of Medicine, University of Cádiz, Plaza Falla 9, 11003, Cadiz, Spain, juanantonio.mico@uca.es.
De Benito
M Dolores
MD
Mico
Juan A
JA
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D002908:Chronic Disease; D004195:Disease Models, Animal; D004347:Drug Interactions; D008297:Male; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists; D010146:Pain / Q000188:drug therapy* / Q000378:metabolism; D017288:Pain Threshold; D010879:Piperazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D011957:Receptors, Opioid / Q000378:metabolism*; D012584:Sciatic Nerve / Q000293:injuries*; D020426:Sciatic Neuropathy / Q000188:drug therapy* / Q000378:metabolism; D058825:Serotonin 5-HT1 Receptor Agonists; D014147:Tramadol / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*
D000701:Analgesics, Opioid; D009292:Narcotic Antagonists; D010879:Piperazines; D011725:Pyridines; D011957:Receptors, Opioid; D058825:Serotonin 5-HT1 Receptor Agonists; D044282:Receptor, Serotonin, 5-HT1A; D009270:Naloxone; D014147:Tramadol; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin