• Brain research · Oct 2002

    Neuropathy-specific analgesic action of intrathecal nicotinic agonists and its spinal GABA-mediated mechanism.

    • Md Haronur Rashid and Hiroshi Ueda.
    • Division of Molecular Pharmacology and Neuroscience, Nagasaki University Graduate School of Biomedical Sciences, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan.
    • Brain Res. 2002 Oct 25;953(1-2):53-62.

    AbstractThe effect of the nicotinic acetylcholine receptor (nAChR) agonists at the spinal level has not been well studied in neuropathic states. In the present report, we demonstrate the efficacy of intrathecal nicotinic agonists in partial sciatic nerve injury-induced neuropathy model mice. Intrathecal (i.t.) administration of (-)nicotine and (+)epibatidine, at doses without undesirable effects, had no antinociceptive action in sham-operated mice. However, they completely reversed the thermal and mechanical hyperalgesia in partial sciatic nerve-injured mice. This neuropathy-specific analgesic action of i.t. (-)nicotine and (+)epibatidine is attributed to different subtypes of nAChRs at the spinal level. After antagonism experiments with mecamylamine, dihydro-beta-erythroidine and methyllycaconitine, it was observed that (-)nicotine-induced analgesia was mediated through the alpha4beta2 subtype of nAChR while the (+)epibatidine-induced one was mediated through non-alpha4beta2 subtype of nAChR. Moreover, i.t. pretreatment with NMDA receptor antagonist did not block nicotinic analgesia. Similar to nicotinic agonists, gamma-aminobutyric acid receptor (GABA(A)) agonist muscimol (i.t.) produced neuropathy-specific analgesic action giving analgesia only in nerve-injured mice. The GABA(A) antagonists bicuculline and picrotoxin significantly blocked the analgesic effects of muscimol as well as that of (-)nicotine and (+)epibatidine. On the other hand, i.t. injection of nicotinic antagonist mecamylamine and GABA(A) antagonist picrotoxin in sham-operated mice induced a thermal hyperalgesia without any effects in nerve-injured animals suggesting the presence of a tonic inhibitory tone on nociceptive transmission through the spinal cholinergic-GABAergic system. These results also suggest that the neuropathy-specific analgesic action of intrathecal nicotinic agonists was due to stimulation of this cholinergic-GABAergic system whose inhibitory tone had been reduced due to injury.

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