Induction of c-fos expression in the mouse brain associated with hyperalgesia induced by intrathecal injection of protein kinase C activator.

Here, we found that a single intrathecal (i.t.) administration of a protein kinase C (PKC) activator, phorbol 12,13-dibutyrate (PDBu), induced pain-like behaviors in mice.

Inhibition of the morphine-induced rewarding effect by direct activation of spinal protein kinase C in mice.

Rationale: We previously demonstrated that the morphine-induced rewarding effect was attenuated under a neuropathic pain-like state following partial sciatic nerve ligation in rodents. Furthermore, the up-regulation of protein kinase C (PKC) activity in the spinal cord is considered to be the key factor for induction of hyperalgesia following sciatic nerve ligation. However, little direct evidence is available for the involvement of activated PKC in the spinal cord in reduction of rewarding effects induced by morphine under chronic pain-like state.

Molecular mechanism of changes in the morphine-induced pharmacological actions under chronic pain-like state: suppression of dopaminergic transmission in the brain.

In the present study, we demonstrated whether a neuropathic pain-like state induced by sciatic nerve ligation in rodents could cause a long-lasting change in intracellular signaling in both supraspinal and spinal cord related to the suppression of morphine's effect. Mice with sciatic nerve ligation exhibited a significant suppression of the morphine-induced antinociception. Under this condition, phosphorylated-conventional protein kinase C-like immunoreactivity (p-cPKC-IR) and phosphorylated-micro-opioid receptor (p-MOR)-IR were clearly increased on the ipsilateral side in the dorsal horn of the spinal cord of nerve-ligated mice.

Increased phosphorylated-mu-opioid receptor immunoreactivity in the mouse spinal cord following sciatic nerve ligation.

The present study was designed to determine whether a state of neuropathic pain induced by sciatic nerve ligation could alter phosphorylated-mu-opioid receptor-like immunoreactivity in the superficial dorsal horn of the mouse spinal cord. Mice with sciatic nerve ligation exhibited a significant suppression of the morphine-induced antinociception. Under this condition, phosphorylated-mu-opioid receptor-like immunoreactivity was clearly increased on the ipsilateral side in the superficial laminae of the L5 lumbar spinal dorsal horn in nerve-ligated mice.