cAMP signaling through protein kinase A and Epac2 induces substance P release in the rat spinal cord.

Using neurokinin 1 receptor (NK1R) internalization to measure of substance P release in rat spinal cord slices, we found that it was induced by the adenylyl cyclase (AC) activator forskolin, by the protein kinase A (PKA) activators 6-Bnz-cAMP and 8-Br-cAMP, and by the activator of exchange protein activated by cAMP (Epac) 8-pCPT-2-O-Me-cAMP (CPTOMe-cAMP). Conversely, AC and PKA inhibitors decreased substance P release induced by electrical stimulation of the dorsal root. Therefore, the cAMP signaling pathway mediates substance P release in the dorsal horn.

Neurokinin 1 receptor activation in the rat spinal cord maintains latent sensitization, a model of inflammatory and neuropathic chronic pain.

Latent sensitization is a model of chronic pain in which a persistent state of pain hypersensitivity is suppressed by opioid receptors, as evidenced by the ability of opioid antagonists to induce a period of mechanical allodynia. Our objective was to determine if substance P and its neurokinin 1 receptor (NK1R) mediate the maintenance of latent sensitization. Latent sensitization was induced by injecting rats in the hindpaw with complete Freund's adjuvant (CFA), or by tibial spared nerve injury (SNI).

A Src family kinase maintains latent sensitization in rats, a model of inflammatory and neuropathic pain.

Latent sensitization is a long-term model of chronic pain in which hyperalgesia is continuously suppressed by opioid receptors, as demonstrated by the induction of mechanical allodynia by opioid antagonists. Different intracellular signals may mediate the initiation, maintenance and expression of latent sensitization. Our criterion for the involvement of a signal in the maintenance of latent sensitization is that inhibitors should permanently eliminate the allodynia produced by an opioid antagonist.

Neuropeptide Y release in the rat spinal cord measured with Y1 receptor internalization is increased after nerve injury.

Neuropeptide Y (NPY) modulates nociception in the spinal cord, but little is known about its mechanisms of release. We measured NPY release in situ using the internalization of its Y1 receptor in dorsal horn neurons. Y1 receptor immunoreactivity was normally localized to the cell surface, but addition of NPY to spinal cord slices increased the number of neurons with Y1 internalization in a biphasic fashion (ECs of 1 nM and 1 μM).

Corticotropin-Releasing Factor in the Brain and Blocking Spinal Descending Signals Induce Hyperalgesia in the Latent Sensitization Model of Chronic Pain.

Latent sensitization is a model of chronic pain in which an injury triggers a period of hyperalgesia followed by an apparent recovery, but in which pain sensitization persists but is suppressed by opioid and adrenergic receptors. One important characteristic of latent sensitization is that hyperalgesia can be triggered by acute stress. To determine whether the effect of stress is mimicked by the activation of corticotropin-releasing factor (CRF) signaling in the brain, rats with latent sensitization induced by injecting complete Freund's adjuvant (CFA, 50 μl) in one hind paw were given an intracerebroventricular (i.