Adenosine inhibits excitatory transmission to substantia gelatinosa neurons of the adult rat spinal cord through the activation of presynaptic A 1 adenosine receptor

Abstract

Although intrathecal administration of adenosine analogues or A 1 adenosine receptor agonists is known to result in antinociception, this has not been examined yet at the cellular level. In the present study, we examined in pharmacology an action of adenosine on glutamatergic miniature excitatory postsynaptic currents (mEPSCs) in substantia gelatinosa (SG) neurons of an adult rat spinal cord slice; this was done under the condition where a postsynaptic action of adenosine was blocked. In 65% of the neurons examined ( n=72), adenosine at a concentration of 100 μM depressed the frequency of mEPSC in a reversible manner; the remaining neurons exhibited an inhibition followed by potentiation of the frequency. When examined quantitatively in extent in some cells ( n=25), the inhibition was 40±3% ( n=25) while the potentiation was 42±8% ( n=6). These actions were not accompanied by a change in mEPSC amplitude. The inhibitory action on mEPSC frequency was dose-dependent in a range of 10–500 μM with an EC 50 value of 277 μM. The inhibitory action of adenosine was mimicked by a selective A 1 adenosine receptor agonist, CPA (1 μM; depression: 54±9%, n=4); this action of adenosine (100 μM) was not observed in the presence of a specific A 1 adenosine receptor antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) (1 μM; 94±4% of control, n=3). The facilitatory action of adenosine (100 μM) was unaffected by an A 2a antagonist, ZM 241385 (0.1 μM, n=3); an A 2a agonist, CGS 21680 (0.1–10 μM; n=6), was without actions on mEPSC frequency. It is concluded that adenosine inhibits excitatory transmission to SG neurons through the activation of presynaptic A 1 adenosine receptor and that some of the inhibition is followed by a potentiation of the transmission. It remains to be examined which subtypes of adenosine receptors except for the A 1- and A 2a-subtypes are involved in the potentiating action. Considering that adenosine-like immunoreactivity and adenosine receptors are expressed at a high density in the SG, which is thought to play an important role in modulating nociceptive transmission from the periphery to the central nervous system, this inhibitory action of adenosine could contribute to a negative modulation of pain transmission.