ABSTRACT
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. OBJECTIVE: The present study was to investigate whether direct activation of spinal PKC by intrathecal (IT) administration of a specific PKC activator, phorbol 12,13-dibutyrate (PDBu) could produce hyperalgesia and suppress the place preference induced by morphine in mice. METHOD: The morphine-induced rewarding effect was investigated using the conditioned place preference method. Conditioning sessions (three for morphine, three for saline) were started 24 h after IT injection of PDBu or saline and conducted once daily for 6 days. On the day after the final conditioning session, a post-conditioning test was performed. RESULTS: IT-administered PDBu produced a long-lasting thermal hyperalgesia. Under these conditions, the place preference induced by morphine was abolished by a single IT pretreatment with PDBu. The effect was reversed by concomitant IT treatment with the specific PKC inhibitor Ro-32-0432. In contrast, IT-administered PDBu failed to affect the hyperlocomotion and supraspinal antinociception induced by morphine. CONCLUSION: The present findings suggest that activated PKC in the spinal cord with chronic pain-like hyperalgesia may play a substantial role in the suppression of the morphine-induced rewarding effect in mice with chronic pain-like hyperalgesia.
Subject(s)
Morphine/pharmacology , Protein Kinase C/metabolism , Reward , Spinal Cord/drug effects , Spinal Cord/enzymology , Animals , Enzyme Activation/drug effects , Enzyme Activation/physiology , Male , Mice , Mice, Inbred ICR , Morphine/antagonists & inhibitors , Motor Activity/drug effects , Motor Activity/physiology , Pain Measurement/drug effects , Pain Measurement/methodsABSTRACT
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. Furthermore, i.t.-administered PDBu caused the increased c-fos-like immunoreactivity in the parafascicular nuclei (PF), amygdala and cingulate cortex (CG), but not hippocampus. These findings suggest that the stimulation of spinal PKC results in an enhancement of neuronal activity in the PF, amygdala and CG associated with hyperalgesia.
Subject(s)
Brain/metabolism , Hyperalgesia/metabolism , Protein Kinase C/metabolism , Proto-Oncogene Proteins c-fos/metabolism , Amygdala/cytology , Amygdala/metabolism , Animals , Brain/cytology , Brain/drug effects , Dose-Response Relationship, Drug , Enzyme Activators , Gyrus Cinguli/cytology , Gyrus Cinguli/metabolism , Hippocampus/cytology , Hippocampus/metabolism , Hyperalgesia/chemically induced , Immunohistochemistry , Injections, Spinal , Intralaminar Thalamic Nuclei/cytology , Intralaminar Thalamic Nuclei/metabolism , Male , Mice , Mice, Inbred ICR , Neural Pathways/cytology , Neural Pathways/drug effects , Neural Pathways/metabolism , Nociceptors/drug effects , Nociceptors/metabolism , Phorbol 12,13-Dibutyrate , Posterior Horn Cells/drug effects , Posterior Horn Cells/metabolism , Protein Kinase C/drug effects , Second Messenger Systems/drug effects , Second Messenger Systems/physiologyABSTRACT
In the present study, we demonstrated the differential role of spinal protein kinases in neuropathic and inflammatory pain. Mice with sciatic nerve ligation exhibited a spinal protein kinase C (PKC)-dependent neuropathic pain-like state. In contrast, an intraplanter injection of inflammatory agent caused a protein kinase A (PKA)-related thermal hyperalgesia. These findings suggest that the substantial activation of spinal PKC and PKA may differentially contribute to the development of respective chronic pain-like state in mice.
