Baclofen, γ-aminobutyric acid(B) receptors and substance P in the mouse spinal cord

Antinociceptive effects of baclofen, a γ-aminobutyric acid(B) (GABA(B)) agonist, were studied in mice along with other GABAergic agents, all administered intrathecally (i.t.): i.e., muscimol (GABA(A) agonist), bicuculline (GABA(A) antagonist) and 5-aminovaleric acid (GABA(B) antagonist). After i.t. administration, none of the four compounds increased the withdrawal latency in the tail-flick test. With the intradermal hypertonic saline (6% saline) behavioral test, baclofen decreased the number of behaviors in a dose-dependent and 5-aminovaleric acid-reversible manner, whereas i.t. administered muscimol was ineffective. With the i.t. substance P (SP) behavioral test, muscimol was again ineffective, whereas the SP-induced behaviors were differentially modified by baclofen depending on the temporal order of their i.t. administration. Although baclofen, coadministered with SP, decreased the number of SP-induced behaviors, baclofen pretreatment (2-100 min before i.t. administration of SP) increased the number of behaviors in a dose-dependent and 5-aminovaleric acid-reversible manner. Two minutes after several fixed doses of baclofen were administered i.t., dose-response curves for induction of behaviors by SP (i.t.) were shifted progressively to the left by increasing doses of baclofen, suggesting that hypersensitivity to SP had developed during this time frame. Decreased responsiveness to a peripheral noxious stimulus (hypertonic saline-induced behavior) is therefore associated with hypersensitivity to i.t. applied SP (SP behavior test). The selective action of a GABA(B) agonist on neurokinin-elicited behaviors shown in this study is in clear contrast to the selective action of a GABA(A) agonist against excitatory amino acid spinal activity noted in the following paper.