Neuropathic pains arising from
peripheral nerve injury can result in increased sensitivity to both noxious and non-noxious stimuli and are accompanied by a number of neuroplastic alterations at the level of the spinal cord including upregulation of
neurotransmitters including
dynorphin,
cholecystokinin and
neuropeptide Y. Additionally, such
pain states appear to be associated with activation of
excitatory amino acid receptors including the
N-methyl-D-aspartate (
NMDA) receptor.
Neuropathic pains have often been classified as '
opioid resistant' in both clinical and laboratory settings. As it is known that
dynorphin produces 'non-
opioid' effects through interaction with
NMDA receptors and this
peptide is upregulated after
peripheral nerve injury, the present studies were undertaken to determine the possible importance of this substance in the neuropathic state. Nerve injury was produced in rats by tight
ligation of the L5 and L6 spinal roots of the sciatic nerve.
Catheters were inserted for the intrathecal (i.t.) delivery of
drug to the lumbar spinal cord.
Tactile allodynia was determined by measuring responses to probing the plantar surface of the affected limb with von Frey filaments, and acute nociception was determined in the 55 degrees C hot-water tail-flick test in nerve-ligated and
sham-operated subjects. Intrathecal administration of
MK-801 or
antisera to
dynorphin A (1-13) did not alter the
tactile allodynia associated with nerve-
ligation injury or the baseline tail-flick latency in either
sham-operated or nerve-injured animals. As previously reported, i.t.
morphine did not alter
tactile allodynia and showed reduced potency and efficacy to block the tail-flick reflex in nerve-injured animals. Co-administration, however, of i.t.
morphine with
MK-801, or i.t.
antisera to
dynorphin A (1-13) given prior to
morphine elicited both a full antiallodynic response and a complete block of the tail-flick reflex in nerve-injured animals. These results suggest that tonic activation of
NMDA receptors, following
peripheral nerve injury, is involved with the attenuation of the effectiveness of spinal
morphine in a model of
neuropathic pain. Additionally, this tonic
NMDA activity may be mediated, in part, by increased levels of endogenous
dynorphin associated with
peripheral nerve injury.