Background: The characterization of neuropathic pain is maladaptive
plasticity within the nociceptive system. Multiple alterations contribute to
complex pain phenotypes. Adrenomedullin (AM) has been documented to be a pain
mediator. However, its involvement in pathological pain is poorly understood. We
studied the contribution of AM to chronic neuropathic pain in the spinal nerve
ligation (SNL) model. Methods: Daily injection of the AM receptor
antagonist AM (10 nmol) via an intrathecal (i.t.) route after SNL
inhibited mechanical allodynia starting on day 6. Single administration of
AM produced an immediate attenuation on pain hypersensitivity on day 2
or 10 post-SNL. Protein and mRNA levels were assayed by immunofluorescent
staining and qRT-PCR, respectively, on days 1, 3, 7 and 15 post-SNL.
Results: The results showed that AM at both protein and mRNA levels was
increased in both injured (L5) and adjacent uninjured (L4) nerves starting on day
3 post-SNL. In dorsal root ganglion (DRG) at L5, AM was increase on days 1–7 at
mRNA level but only on day 7 at protein level. However, AM was increase at mRNA
level on days 1–7 and at protein level on days 3–15 in L4 DRG. AM mRNA
expression was upregulated on days 1–7 in the spinal cord. Expression of
receptor activity-modifying protein 2 (RAMP2), an essential AM1 receptor
component, was upregulated in small and medium-diameter neurons on days 1–15 in
both L5 and L4 DRG. Furthermore, single administration of AM suppressed
the increase of nNOS in DRG induced by SNL and daily injection of AM
for 7 days inhibited SNL-induced increase of CGRP mRNA in the spinal dorsal
horn. Conclusions: This study indicates that the increased AM
bioactivity in injured and uninjured peripheral nerves, uninjured adjacent DRG
and the spinal dorsal horn play a critical role mainly in the late-phase
development of neuropathic pain. The mechanism may involve the recruitment of
nNOS and CGRP.