Modulation of the hyperpolarization-activated current (I-h) by cyclic nucleotides in guinea-pig primary afferent neurons

1. Whole-cell patch-clamp recordings were made from dissociated guinea-pig nodose and trigeminal ganglion neurons in culture to study second messenger mechanisms of the hyperpolarization-activated current (I-h) modulation. 2. Prostaglandin E(2) (PGE(2)) and forskolin modulate I-h in primary afferents by shifting the activation curve in the depolarizing direction and increasing the maximum amplitude. 3. The cAMP analogues, RP-cAMP-S (an inhibitor of protein kinase A (PKA)) and SP-cAMP-S (an activator of PKA), both shifted the activation curve of I-h to more depolarized potentials and occluded the effects of forskolin. These results suggest that I-h is modulated by a direct action of the cAMP analogues. 4. Superfusion of other cyclic nucleotide analogues (8-Br-cAMP, 8-(4-chlorophenylthio)-cAMP and 8-Br-cGMP) mimicked the actions of forskolin and PGE(2), but dibutyryl cGMP, 5'-AMP and adenosine had no effect on I-h. 8-Br-cAMP and 8-Br-cGMP had similar concentration response profiles, suggesting that I-h has little nucleotide selectivity. 5. The inhibitor peptide (PKI), the catalytic subunit of PKA (C subunit) and phosphatase inhibitors (microcystin and okadaic acid) had no effect on forskolin modulation of I-h. 6. These results indicate that I-h is regulated by cyclic nucleotides in sensory neurons. Positive regulation of I-h by prostaglandins produced during inflammation may lead to depolarization and facilitation of repetitive activity, and thus contribute to sensitization to painful stimuli.