Implication of spinal protein kinase Cγ isoform in activation of the mouse brain by intrathecal injection of the protein kinase C activator phorbol 12,13-dibutyrate using functional magnetic resonance imaging analysis

The aim of the present study was to investigate whether direct activation of protein kinase C (PKC) in the spinal cord could change brain activation using a functional magnetic resonance imaging (fMRI) analysis in mice that lack the PKCγ gene. The activation of spinal PKC by intrathecal (i.t.) injection with phorbol 12,13-dibutyrate (PDBu), a specific PKC activator, caused a time-dependent decrease in paw-withdrawal latency to the heat thermal stimulus. In contrast, i.t. injection of PDBu failed to cause thermal hyperalgesia in mice which lacked the PKCγ gene. We found that the i.t. injection with PDBu caused a remarkable increase in the activity of several brain regions in wild-type mice compared with vehicle injection. In the somatosensory cortex and lateral and medial thalamus, i.t. injection of PDBu produced a dramatic and time-dependent increase in signal intensity at 1-6 h after i.t. PDBu injection. In contrast, i.t. injection of PDBu produced a delayed but significant increase in signal intensity at 3-6 h in the cingulate cortex, at 4-6 h in the nucleus accumbens and at 3-6 h in the ventral tegmental area. In addition, all effects of PDBu were abolished in mice that lacked the PKCγ gene. These results suggest that the activation of spinal PKCγ associated with the activation of ascending pain transmission may be an important factor in chronic pain-like hyperalgesia with changes in emotionality.