Diminished Inflammation and Nociceptive Pain with Preservation of Neuropathic Pain in Mice with a Targeted Mutation of the Type I Regulatory Subunit of cAMP-Dependent Protein Kinase

TLDR

The RIβ regulatory subunit is expressed only in the nervous system, particularly in small‑diameter trkA‑positive dorsal root ganglion neurons, and is proposed to mediate nociceptive processing during inflammatory conditions. The study aimed to determine how PKA contributes to injury‑induced inflammation and pain by evaluating nociceptive responses in mice lacking the neuronal RIβ subunit. The authors used a RIβ null mouse model to assess nociceptive responses following tissue injury and inflammatory stimuli. RIβ PKA is essential for full expression of injury‑evoked nociceptive pain—mutant mice display normal acute pain but markedly reduced persistent pain behavior, hindpaw inflammation, dorsal horn Fos activation, plasma extravasation, and prostaglandin‑induced thermal sensitivity—while nerve‑injury–evoked neuropathic pain remains unaffected.

Abstract

To assess the contribution of PKA to injury-induced inflammation and pain, we evaluated nociceptive responses in mice that carry a null mutation in the gene that encodes the neuronal-specific isoform of the type I regulatory subunit (RIβ) of PKA. Acute pain indices did not differ in the RIβ PKA mutant mice compared with wild-type controls. However, tissue injury-evoked persistent pain behavior, inflammation of the hindpaw, and ipsilateral dorsal horn Fos immunoreactivity was significantly reduced in the mutant mice, as was plasma extravasation induced by intradermal injection of capsaicin into the paw. The enhanced thermal sensitivity observed in wild-type mice after intraplantar or intrathecal (spinal) administration of prostaglandin E 2 was also reduced in mutant mice. In contrast, indices of pain behavior produced by nerve injury were not altered in the mutant mice. Thus, RIβ PKA is necessary for the full expression of tissue injury-evoked (nociceptive) pain but is not required for nerve injury-evoked (neuropathic) pain. Because the RIβ subunit is only present in the nervous system, including small diameter trkA receptor-positive dorsal root ganglion cells, we suggest that in inflammatory conditions, RIβ PKA is specifically required for nociceptive processing in the terminals of small-diameter primary afferent fibers.