Opioid receptors are major actors in
pain control and are broadly distributed throughout the nervous system. A major challenge in
pain research is the identification of key
opioid receptor populations within nociceptive pathways, which control physiological and pathological
pain. In particular, the respective contribution of peripheral vs. central receptors remains unclear, and it has not been addressed by genetic approaches. To investigate the contribution of peripheral
delta opioid receptors in
pain control, we created conditional knockout mice where
delta receptors are deleted specifically in peripheral Na(V)1.8-positive primary nociceptive neurons. Mutant mice showed normal
pain responses to acute heat and to mechanical and
formalin stimuli. In contrast, mutant animals showed a remarkable increase of
mechanical allodynia under both inflammatory
pain induced by complete
Freund adjuvant and
neuropathic pain induced by partial sciatic nerve
ligation. In these 2 models, heat
hyperalgesia was virtually unchanged.
SNC80, a delta agonist administered either systemically (complete
Freund adjuvant and sciatic nerve
ligation) or into a paw (sciatic nerve
ligation), reduced
thermal hyperalgesia and
mechanical allodynia in control mice. However, these
analgesic effects were absent in conditional mutant mice. In conclusion, this study reveals the existence of
delta opioid receptor-mediated mechanisms, which operate at the level of Na(V)1.8-positive nociceptive neurons.
Delta receptors in these neurons tonically inhibit mechanical
hypersensitivity in both inflammatory and
neuropathic pain, and they are essential to mediate delta
opioid analgesia under conditions of persistent
pain. This
delta receptor population represents a feasible therapeutic target to alleviate
chronic pain while avoiding adverse central effects. The conditional knockout of
delta-opioid receptor in primary afferent Na(V)1.8 neurons augmented
mechanical allodynia in persistent
pain models and abolished delta
opioid analgesia in these models.