A pharmacologic analysis of mechanical hyperalgesia in streptozotocin/diabetic rats.
This study used streptozotocin (STZ; 50 mg/kg i.p.) diabetic rats and monitored weekly thermal and mechanical nociceptive thresholds for 8 weeks diabetes. Rats developed mechanical hyperalgesia as soon as 2 weeks after STZ injection. Thermal nociceptive threshold was not altered up to 8 weeks after STZ injection. Four week-diabetic rat mechanical hyperalgesia showed reduced sensitivity to the antinociceptive effect of morphine (5-20 mg/kg i.p.). Furthermore, a reduced sensitivity to the antinociceptive effect of the GABA(B) agonist, (+/-)baclofen, was observed. A dose as high as 16 mg/kg i.p. of (+/-)baclofen was necessary to reverse 4 week-diabetic rat hyperalgesia, whereas in control rats the highest antinociceptive dose devoid of muscle-relaxant effect was 4 mg/kg i.p. The non-peptide antagonist for the substance P, neurokinin, (NK1) receptor, RP 67580 (3-9 mg/kg i.p.) was not effective in reversing the mechanical hyperalgesia associated with 4 week-diabetes. A six day-treatment with an antagonist for the N-methyl-D-aspartate (NMDA) receptor for glutamate, (+)MK-801 (0.1 mg/kg i.p. twice a day), gradually but completely reversed 4 week-diabetes-induced mechanical hyperalgesia. These data suggest that diabetes-induced hyperalgesia may be the consequence of increased activity of primary afferent fibres leading to an increased excitatory tone within the spinal cord. An increased release of glutamate and activation of the NMDA receptor, would maintain the hyperalgesic state. Reduced activity of both opioidergic and GABA(B)ergic inhibitory systems, might exacerbate the increased excitation thus contributing to the ongoing pain. It is suggested that NMDA receptor antagonists may constitute an alternative therapy for diabetic neuropathic pain.
Malcangio
M
M
Department of Pharmacology, St. Bartholomew's and the Royal London School of Medicine and Dentistry, Queen Mary and Westfield College, UK. m.a.m.malcangio@mds.qmw.ac.uk
Tomlinson
D R
DR
D000818:Animals; D001418:Baclofen / Q000494:pharmacology; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000523:psychology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018755:GABA Agonists / Q000494:pharmacology; D058786:GABA-B Receptor Agonists; D006930:Hyperalgesia / Q000188:drug therapy* / Q000209:etiology* / Q000523:psychology; D007211:Indoles / Q000494:pharmacology; D054833:Isoindoles; D008297:Male; D064729:Neurokinin-1 Receptor Antagonists; D010812:Physical Stimulation; D011312:Pressure; D051381:Rats; D017208:Rats, Wistar; D012584:Sciatic Nerve / Q000187:drug effects / Q000378:metabolism; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism; D013373:Substance P / Q000378:metabolism
D001786:Blood Glucose; D018755:GABA Agonists; D058786:GABA-B Receptor Agonists; D007211:Indoles; D054833:Isoindoles; D064729:Neurokinin-1 Receptor Antagonists; C071693:7,7-diphenyl-2-(1-imino-2-(2-methoxyphenyl)ethyl)perhydroisoindol-4-one; D013373:Substance P; D016291:Dizocilpine Maleate; D001418:Baclofen