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

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 neuronalspecific isoform of the type I regulatory subunit (RI␤) of PKA. Acute pain indices did not differ in the RI␤ PKA mutant mice compared with wild-type controls. However, tissue injuryevoked 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, RI␤ 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 RI␤ subunit is only present in the nervous system, including small diameter trkA receptor-positive dorsal root ganglion cells, we suggest that in inflammatory conditions, RI␤ PKA is specifically required for nociceptive processing in the terminals of small-diameter primary afferent fibers.

Anandamide-Evoked Activation of Vanilloid Receptor 1 Contributes to the Development of Bladder Hyperreflexia and Nociceptive Transmission to Spinal Dorsal Horn Neurons in Cystitis

“…Previous data support this assumption, because both PKA and PKC, which are activated in inflammation (Malmberg et al, 1997;Zhou et al, 2003), induce phosphorylation of the CB1 receptor, which results in reduced CB1 receptor activity (Garcia et al, 1998;Huang et al, 2002). Because both PKA and PKC increase both the potency and efficacy of anandamide on TRPV1 (Premkumar and Ahern, 2000;De Petrocellis et al, 2001), anandamide could excite capsaicin-sensitive bladder afferents in inflammatory conditions at a significantly lower concentration than we observed in the present study on naive bladders.…”

“…Although in physiological conditions, the excitatory effect of anandamide on primary sensory neurons is weak, it is significantly increased when inflammatory conditions are replicated in primary sensory neuronal cultures by activating protein kinase A (PKA), protein kinase C (PKC), or phospholipase C (PLC) (Malmberg et al, 1997;Zygmunt et al, 1999;Chuang et al, 2001;Ahluwalia et al, 2003b;Zhou et al, 2003). Moreover, Ca 2ϩ influx into capsaicin-sensitive primary sensory neurons, which occurs in inflammation (Linhart et al, 2003), results in the production of anandamide, the amount of which is comparable with that evoking TRPV1-mediated excitation of primary sensory neurons after PKA, PKC, and PLC activation in the cells (Premkumar and Ahern, 2000;Chuang et al, 2001;De Petrocellis et al, 2001;Ahluwalia et al, 2003a,b).…”

Downregulation of Transient Receptor Potential Melastatin 8 by Protein Kinase C-Mediated Dephosphorylation

“…Sensitization of TRPV1 by inflammatory mediators acting via PKC, protein kinase A, and receptor tyrosine kinase has been shown to underlie hyperalgesia (Malmberg et al, 1997;Lopshire and Nicol, 1998;Cesare et al, 1999a,b;Khasar et al, 1999;Premkumar and Ahern, 2000;Chuang et al, 2001;Bhave et al, 2002;Numazaki et al, 2002;Wang et al, 2004). Here, we have demonstrated downregulation of TRPM8 by dephosphorylation of the receptor by activation of PKC.…”

PKA-Induced Internalization of Slack KNaChannels Produces Dorsal Root Ganglion Neuron Hyperexcitability

“…Inflammatory mediators such as prostaglandin E2 (PGE 2 ) (Hingtgen et al, 1995), produce hyperalgesia through the activation of PKA Khasar et al, 1998Khasar et al, , 1999Schnizler et al, 2008). The importance of PKA during inflammatory pain has been clearly established (Malmberg et al, 1997). Ion channel modulation by PKA is, therefore, responsible for the intrinsic plasticity associated with nociceptor sensitization (Taiwo et al, 1989(Taiwo et al, , 1992Taiwo and Levine, 1991).…”