The co-administration of
morphine at spinal (i.th.) and supraspinal (i.c.v.) sites to the same rat produces antinociceptive synergy, a phenomenon which may underlie the clinical
analgesic utility of this
drug. In animals with
peripheral nerve injury, however, the antinociceptive potency and efficacy of i.th.
morphine is significantly decreased. Here, the possible loss of spinal/supraspinal
morphine antinociceptive synergy and relationship to elevation of spinal
dynorphin content was studied.
Ligation of lumbar spinal nerves resulted in elevated
dynorphin in the ipsilateral lumbar and sacral spinal cord. In
sham-operated rats supraspinal/spinal co-administration of
morphine produced synergistic antinociception which was unaffected by i.th.
MK-801 or
dynorphin A((1-17)) antiserum. In nerve-injured rats, i.th.
morphine was inactive against
tactile allodynia and showed diminished in potency against acute nociception without supraspinal/spinal antinociceptive synergy. Antiserum to
dynorphin A((1-17)) or the non-competitive
NMDA antagonist
MK-801 increased the antinociceptive potency of i.th.
morphine, restored supraspinal/spinal
morphine antinociceptive synergy and elicited a dose-related i.th.
morphine antiallodynic action. These agents did not demonstrate antinociceptive or antiallodynic activity alone and did not alter
morphine actions in
sham-operated animals. The loss of spinal/supraspinal antinociceptive synergy and lack of antiallodynic activity of spinal
morphine appear to be due to the elevation across multiple spinal segments of
dynorphin following nerve injury. Pathological actions of elevated
dynorphin may directly or indirectly modulate the
NMDA receptor, result in a loss of supraspinal/spinal
morphine synergy and may thus account for the decreased clinical
analgesic efficacy of
morphine in
peripheral neuropathies.