Relationship between the antinociceptive response to desipramine and changes in GABAB receptor function and subunit expression in the dorsal horn of the rat spinal cord.
Although tricyclic antidepressants are among the drugs of choice for the treatment of neuropathic pain, their mechanism of action in this regard remains unknown. Because previous reports suggest these agents may influence gamma-aminobutyric acid (GABA) neurotransmission, and GABAB receptors are known to participate in the transmission of pain impulses, the present experiments were undertaken to examine whether the administration of desipramine alters GABAB receptor subunit expression and function in the dorsal horn of the rat spinal cord. For the study, rats were injected (i.p.) once daily with desipramine (15 mg/kg) for 7 consecutive days, during which their thermal withdrawal threshold was monitored, and after which GABAB receptor function, and the levels of GABAB receptor subunit mRNA, were quantified in the spinal cord dorsal horn. The results indicate that 4-7 days of continuous administration of desipramine are necessary to observe a significant increase in the thermal pain threshold. Moreover, it was found that 7 days of treatment with desipramine enhances GABAB receptor function, as measured by baclofen-stimulated [35S]GTPgammaS binding, and increases mRNA expression for the GABAB(1a) and GABAB(2), but not GABAB(1b), subunits. These findings suggest the antinociceptive effect of desipramine is accompanied by a change in spinal cord GABAB receptor sensitivity that could be an important component in the analgesic response to this agent.
Sands
Scott A
SA
Department Pharmacology, Toxicology and Therapeutics, Kansas University School of Medicine, 3901 Rainbow Blvd., Mail Code 1018, Kansas City, KS 66160, USA.
McCarson
Kenneth E
KE
Enna
S J
SJ
D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology; D001418:Baclofen / Q000494:pharmacology; D003891:Desipramine / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects*; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D008297:Male; D020671:Posterior Horn Cells / Q000187:drug effects* / Q000378:metabolism; D021122:Protein Subunits / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018080:Receptors, GABA-B / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D013116:Spinal Cord / Q000166:cytology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D000700:Analgesics; D000929:Antidepressive Agents, Tricyclic; D021122:Protein Subunits; D018080:Receptors, GABA-B; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D005680:gamma-Aminobutyric Acid; D001418:Baclofen; D003891:Desipramine