Cyclic AMP mediates the prostaglandin E2-induced potentiation of bradykinin excitation in rat sensory neurons

doi:10.1016/0306-4522(94)00567-O

Neuroscience

Volume 66, Issue 2, May 1995, Pages 459-466

https://doi.org/10.1016/0306-4522(94)00567-O Get rights and content

Abstract

Prostaglandins enhance the sensitivity of sensory neurons to excitatory chemical agents such as bradykinin. The intracellular transduction cascades mediating this potentiation remain largely unknown. We have examined the role of cyclic AMP in the prostaglandin E₂-induced potentiation of sensory neurons. Pretreatment with agents that elevate intracellular cyclic AMP levels enhances the number of action potentials elicited by bradykinin in a manner analogous to that of prostaglandin E₂. The prostaglandin E₂-induced potentiation of the number of bradykinin-elicited action potentials is blocked by either inhibition of adenylyl cyclase or protein kinase A.

Therefore, our results suggest that prostaglandin E₂ activates adenylyl cyclase to increase intracellular cyclic AMP, which in turn activates protein kinase A. Presumably activation of protein kinase A leads to increased levels of protein phosphorylation that then contribute to the enhancement of neuronal sensitivity to excitatory chemical agents.

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Cited by (97)

Variability in analgesic response to non-steroidal anti-inflammatory drugs
2018, Prostaglandins and Other Lipid Mediators
Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most commonly used agents for the treatment of acute and chronic pain. However, it has long been recognized that there is substantial inter-individual variability in the analgesic response to NSAIDs, reflecting the complex interplay between mechanisms of pain, differences between distinct NSAIDs, and patient-specific factors such as genetic variation. This review summarizes the current knowledge regarding how these factors contribute to variability in the analgesic response to NSAIDs.
PKA is required for the modulation of spinal nociceptive information related to ephrinB-EphB signaling in mice
2015, Neuroscience
EphB receptors and their ephrinB ligands are implicated in modulating of spinal nociceptive information processing. Here, we investigated whether protein kinase A (PKA), acts as a downstream effector, participates in the modulation spinal nociceptive information related to ephrinB–EphB signaling. Intrathecal injection of ephrinB2-Fc caused thermal hyperalgesia and mechanical allodynia, which were accompanied by increased expression of spinal PKA catalytic subunit (PKAca) and phosphorylated cAMP-response element-binding protein (p-CREB). Pre-treatment with H89, a PKA inhibitor, prevented the activation of CREB by ephrinB2-Fc. Inhibition of spinal PKA signaling prevented and reversed pain behaviors induced by the intrathecal injection of ephrinB2-Fc. Furthermore, blockade of the EphB receptors by intrathecal injection of EphB2-Fc reduced formalin-induced inflammatory, chronic constrictive injury (CCI)-induced neuropathic, and tibia bone cavity tumor cell implantation (TCI)-induced bone cancer pain behaviors, which were accompanied by decreased expression of spinal PKAca and p-CREB. Overall, these results confirmed the important involvement of PKA in the modulation of spinal nociceptive information related to ephrinBs–EphBs signaling. This finding may have important implications for exploring the roles and mechanisms of ephrinB–EphB signaling in physiologic and pathologic pain.
Prostaglandin transporting protein-mediated prostaglandin E<inf>2</inf> transport in lipopolysaccharide-inflamed rat dental pulp
2014, Journal of Endodontics
Citation Excerpt :
First, it has hyperalgesic effects, which sensitize the nociceptive nerve endings (29). Second, it can increase the pain response to other pain mediators such as bradykinin (30). Moreover, the PGE2 level is correlated with the histologic degree of human pulp inflammation and thus might be useful for distinguishing between reversible and irreversible pulpitis (9).
The prostaglandin transporter (Pgt) and multidrug resistance-associated protein (Mrp) 4 are membrane transport proteins that play crucial roles in the transmembrane uptake and/or efflux of prostaglandins (PGs). This study attempted to analyze the protein expression of Pgt and Mrp4 and their involvement in PGE₂ efflux transport in lipopolysaccharide (LPS)-inflamed rat incisor pulp tissue.
Pulpitis was induced in the upper incisors of Wistar rats by treating them with LPS for 24 hours. The protein expression levels of Pgt, Mrp4, and microsomal PGE synthase (mPGES) were analyzed with immunofluorescent staining. The amount of PGE₂ released from the inflamed pulp tissue in the presence or absence of dipyridamole (an Mrp4 inhibitor) was assessed by using an enzyme-linked immunosorbent assay.
Double immunofluorescence staining revealed that the Pgt, Mrp4, and mPGES immunoreactivity co-localized in CD31-expressing endothelial cells. Moreover, the Mrp4 inhibitor caused a significant decrease in the amount of PGE₂ released from the LPS-inflamed pulp (P < .01 at 24 hours).
Pgt, Mrp4, and mPGES expression was detected in the endothelial cells of normal and LPS-inflamed rat incisor pulp tissue, suggesting that these cells are associated with the biosynthesis and transmembrane transport of PGE₂. The significant decrease in PGE₂ release induced by the Mrp4 inhibitor suggests that Mrp4 contributes to the transport of PGE₂ in the transmembrane efflux pathway.
Prostanoids and inflammatory pain
2013, Prostaglandins and Other Lipid Mediators
Citation Excerpt :
There is evidence that PKA phosphorylation mainly contributes to the early phase of hyperalgesia evoked by peripheral PGE2 administration, while PKC largely effects the late phase of PGE2-evoked hyperalgesia [63]. In addition to modulating directly ion channels, PGE2 also possesses indirect effects, including enhancing the sensitivity of peripheral neurons to other excitatory chemical agents such as bradykinin acting on B2-receptors [64,65] or capsaicin acting on TRPV1-receptors [66]. Although PGE2 alone did not produce spontaneous pain in human volunteers, a small dose of PGE2 injected subcutaneously evoked long-lasting hyperalgesia to mechanical and chemical stimuli [67].
Prostanoids play pivotal roles in inflammation and pain. Cyclooxygenase (COX) inhibitors, the nonsteroidal anti-inflammatory drugs (NSAIDs), depress prostanoid formation and are widely used to treat inflammatory pain. However, their therapeutic benefit is offset by serious side-effects, primarily gastrointestinal and cardiovascular complications. Pathway elements downstream of the COX enzymes, particularly the terminal synthases and receptors of prostaglandin E₂, have been proposed as alternative targets for the development of novel NSAID like drugs. Here, we summarize the current knowledge on the roles of individual prostanoids in modulating inflammatory pain.
TRP and ASIC channels mediate the antinociceptive effect of citronellyl acetate
2013, Chemico-Biological Interactions
Citation Excerpt :
During inflammation, prostaglandins are released into the bloodstream and increase the levels of intracellular cyclic adenosine monophosphate (cAMP) in sensory neurons [44]. This effect can be mimicked by the addition of membrane-permeable cAMP analogs [45]. NSAIDs and opiates decrease cAMP levels.
Background
Citronellyl acetate (CAT), a monoterpene product of the secondary metabolism of plants, has been shown in the literature to possess several different biological activities. However, no antinociceptive abilities have yet been discussed. Here, we used acute pain animal models to describe the antinociceptive action of CAT.
Methods
The acetic acid-induced writhing test and the paw-licking test, in which paw licking was induced by glutamate and formalin, were performed to evaluate the antinociceptive action of CAT and to determine the involvement of PKC, PKA, TRPV1, TRPA1, TRPM8 and ASIC in its antinociceptive mechanism. To do so, we induced paw-linking using agonists.
Results
CAT was administered intragastrically (25, 50, 75, 100 and 200 mg/kg), and the two higher doses caused antinociceptive effects in the acetic acid model; the highest dose reduced pain for 4 h after it was administered (200 mg/kg). In the formalin test, two doses of CAT promoted antinociception in both the early and later phases of the test. The glutamate test showed that its receptors are involved in the antinociceptive mechanism of CAT. Pretreatment with CAT did not alter locomotor activity or motor coordination. In an investigation into the participation of TRP channels and ASICs in CAT’s antinociceptive mechanism, we used capsaicin (2.2 μg/paw), cinnamaldehyde (10 mmol/paw), menthol (1.2 mmol/paw) and acidified saline (2% acetic acid, pH 1.98). The results showed that TRPV1, TRPM8 and ASIC, but not TRPA1, are involved in the antinociceptive mechanism. Finally, the involvement of PKC and PKA was also studied, and we showed that both play a role in the antinociceptive mechanism of CAT.
Conclusion
The results of this work contribute information regarding the antinociceptive properties of CAT on acute pain and show that, at least in part, TRPV1, TRPM8, ASIC, glutamate receptors, PKC and PKA participate in CAT’s antinociceptive mechanism.
TRP channels and analgesia
2013, Life Sciences
Since cloning and characterizing the first nociceptive ion channel Transient Receptor Potential (TRP) Vanilloid 1 (TRPV1), other TRP channels involved in nociception have been cloned and characterized, which include TRP Vanilloid 2 (TRPV2), TRP Vanilloid 3 (TRPV3), TRP Vanilloid 4 (TRPV4), TRP Ankyrin 1 (TRPA1) and TRP Melastatin 8 (TRPM8), more recently TRP Canonical 1, 5, 6 (TRPC1, 5, 6), TRP Melastatin 2 (TRPM2) and TRP Melastatin 3 (TRPM3). These channels are predominantly expressed in C and Aδ nociceptors and transmit noxious thermal, mechanical and chemical sensitivities. TRP channels are modulated by pro-inflammatory mediators, neuropeptides and cytokines. Significant advances have been made targeting these receptors either by antagonists or agonists to treat painful conditions. In this review, we will discuss TRP channels as targets for next generation analgesics and the side effects that may ensue as a result of blocking/activating these receptors, because they are also involved in physiological functions such as release of vasoactive neuropeptides and regulation of vascular tone, maintenance of the body temperature, gastrointestinal motility, urinary bladder control, etc.

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^*: Current address: Department of Physiology and Cell Biology, University of Texas Medical School at Houston, Houston, TX 77225, U.S.A.

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Neuroscience

Abstract

References (28)

A potent synthetic peptide inhibitor of the cAMP-dependent protein kinase

J. biol. Chem.

I. Prostaglandin hyperalgesia, a cAMP/Ca²⁺ dependent process

Prostaglandins

Prostaglandin E receptors in bovine adrenal medulla are coupled to adenylate cyclase via G_i and to phosphoinositide metabolism in a pertussis toxin-insensitive manner

J. biol. Chem.

Prostaglandins sensitize nociceptors in cell culture

Neurosci. Lett.

Mediation of primary afferent peripheral hyperalgesia by the cAMP second messenger system

Neuroscience

Some rat sensory neurons in culture express characteristics of differentiated pain sensory cells

The effects of bradykinin and prostaglandin E₁ on rat cutaneous afferent nerve activity

Br. J. Pharmac.

Actions of capsaicin on peripheral nociceptors of the neonatal rat spinal cord-tail in vitro: dependence of extracellular ions and independence of second messengers

Br. J. Pharmac.

Bradykinin-induced activation of nociceptors: receptor and mechanistic studies on the neonatal rat spinal cord-tail preparation in vitro

Br. J. Pharmac.

Forskolin prolongs action potential duration and blocks potassium current in embryonic chick sensory neurons

Pflüger's Arch.

Prostaglandins, aspirin-like drugs and analgesia

Nature New Biol.

Reversal of synaptic depression by serotonin at Aplysia sensory neuron synapses involves activation of adenylyl cyclase

Activators of adenylate cyclase and cyclic AMP prolong calcium-dependent action potentials of mouse sensory neurons in culture by reducing a voltage-dependent potassium conductance

J. Neurosci.

Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches

Pflüger's Arch.

Cited by (97)

Variability in analgesic response to non-steroidal anti-inflammatory drugs

PKA is required for the modulation of spinal nociceptive information related to ephrinB-EphB signaling in mice

Prostaglandin transporting protein-mediated prostaglandin E<inf>2</inf> transport in lipopolysaccharide-inflamed rat dental pulp

Prostanoids and inflammatory pain

TRP and ASIC channels mediate the antinociceptive effect of citronellyl acetate

TRP channels and analgesia

Cyclic AMP mediates the prostaglandin E2-induced potentiation of bradykinin excitation in rat sensory neurons

Abstract

J. biol. Chem.

Prostaglandins

J. biol. Chem.

Neurosci. Lett.

Neuroscience

Some rat sensory neurons in culture express characteristics of differentiated pain sensory cells

The effects of bradykinin and prostaglandin E1 on rat cutaneous afferent nerve activity

Br. J. Pharmac.

Actions of capsaicin on peripheral nociceptors of the neonatal rat spinal cord-tail in vitro: dependence of extracellular ions and independence of second messengers

Br. J. Pharmac.

Bradykinin-induced activation of nociceptors: receptor and mechanistic studies on the neonatal rat spinal cord-tail preparation in vitro

Br. J. Pharmac.

Forskolin prolongs action potential duration and blocks potassium current in embryonic chick sensory neurons

Pflüger's Arch.

Prostaglandins, aspirin-like drugs and analgesia

Nature New Biol.

Reversal of synaptic depression by serotonin at Aplysia sensory neuron synapses involves activation of adenylyl cyclase

Activators of adenylate cyclase and cyclic AMP prolong calcium-dependent action potentials of mouse sensory neurons in culture by reducing a voltage-dependent potassium conductance

J. Neurosci.

Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches

Pflüger's Arch.

Cyclic AMP mediates the prostaglandin E₂-induced potentiation of bradykinin excitation in rat sensory neurons

The effects of bradykinin and prostaglandin E₁ on rat cutaneous afferent nerve activity