Studies in experimental models and controlled patient trials indicate that
opioids are effective in managing
neuropathic pain. However, side effects secondary to their central nervous system actions present barriers to their clinical use. Therefore, we examined whether activation of the peripheral
mu-opioid receptors (MORs) could effectively alleviate
neuropathic pain in rats after L5 spinal nerve
ligation (SNL). Systemic
loperamide hydrochloride (0.3-10 mg/kg, s.c.), a peripherally acting MOR-preferring agonist, dose-dependently reversed the
mechanical allodynia at day 7 post-SNL. This anti-allodynic effect produced by systemic
loperamide (1.5mg/kg, s.c.) was blocked by systemic pretreatment with either
naloxone hydrochloride (10 mg/kg, i.p.) or methyl-
naltrexone (5 mg/kg, i.p.), a peripherally acting MOR-preferring antagonist. It was also blocked by ipsilateral intraplantar pretreatment with methyl-
naltrexone (43.5 microg/50 microl) and the highly selective MOR antagonist CTAP (5.5 microg/50 microl). However, this anti-allodynic effect of systemic
loperamide was not blocked by intraplantar pretreatment with the
delta-opioid receptor antagonist
naltrindole hydrochloride (45.1 microg/50 microl). The anti-allodynic potency of systemic
loperamide varied with time after nerve injury, with similar potency at days 7, 28, and 42 post-SNL, but reduced potency at day 14 post-SNL. Ipsilateral intraplantar injection of
loperamide also dose-dependently (10-100 microg/50 microl) reversed
mechanical allodynia on day 7 post-SNL. We suggest that
loperamide can effectively attenuate
neuropathic pain, primarily through activation of peripheral MORs in local tissue. Therefore, peripherally acting MOR agonists may represent a promising therapeutic approach for alleviating
neuropathic pain.