The endogenous opioid peptide dynorphin A has non-opioid effects that can damage the spinal cord when given in high doses. Dynorphin has been shown to increase the receptive field size of spinal cord neurons and facilitate C- fiber-evoked reflexes. Furthermore, endogenous dynorphin levels increase following damage to the spinal cord, injury to peripheral nerves, or inflammation. In this study, sensory processing was characterized following a single, intrathecal injection of dynorphin A (1-17) in mice. A single intrathecal injection of dynorphin A (1-17) (3 nmol, i.t.) induced mechanical allodynia (hind paw, von Frey filaments) lasting 70 days, tactile allodynia (paint brush applied to flank) lasting 14 days, and cold allodynia (acetone applied to the dorsal hind paw) lasting 7 days. Similarly, dynorphin A (2- 17) (3 nmol, i.t.), a non-opioid peptide, induced cold and tactile allodynia analogous to that induced by dynorphin A (1-17), indicating the importance of non-opioid receptors. Pretreatment with the NMDA antagonists, MK-801 and LY235959, but not the opioid antagonist, naloxone, blocked the induction of allodynia. Post-treatment with MK-801 only transiently blocked the dynorphin- induced allodynia, suggesting the NMDA receptors may be involved in the maintenance of allodynia as well as its induction. We have induced a long- lasting state of allodynia and hyperalgesia by a single intrathecal injection of dynorphin A (1-17) in mice. The allodynia induced by dynorphin required NMDA receptors rather than opioid receptors. This result is consistent with results in rats and with signs of clinically observed neuropathic pain. This effect of exogenously administered dynorphin raises the possibility that increased levels of endogenous dynorphins associated with spinal cord injuries may participate in the genesis and maintenance of neuropathic pain.
Bibliographical noteFunding Information:
We thank Kelley F. Kitto for outstanding technical support. LY235959 was a generous gift from the Eli Lilly Company, dynorphin A (1-17) was a generous gift from NIDA, and dynorphin A (2-17) was a generous gift from Dr. Victor Hruby. This study was supported by NIDA/K02-DA-00145 and NIDA/R01-DA-04274 to G.L.W.; NIDA training grant T32 DA07097 supported T.M.L. This study was also supported in part by DA 06284 and DA 04248; F.P. is the recipient of an RSDA (KO2 DA00185) from NIDA.
- Dynorphin A
- Spinal cord