18. Repeated morphine enhances peripheral nerve injury-induced allodynia via central immune mechanisms

• Published in: Brain, behavior, and immunity behavior, and immunity, 2013-09, Vol.32, p.e5-e6
• Main Authors: Grace, P.M, Greene, L.I, Strand, K.A, Rice, K.C, Maier, S.F, Watkins, L.R
• Format: Article
• Language: English
• Subjects: Allergy and Immunology; Psychiatry
• ISSN: 0889-1591; 1090-2139
• DOI: 10.1016/j.bbi.2013.07.030

Glial activation occurs after morphine and peripheral nerve injury alone, but the behavioral and molecular impact in tandem is unknown. We predicted that sciatic chronic constriction injury (CCI)-allodynia would be enhanced by subsequent repeated morphine, in a Toll-like Receptor 4 [TLR4]-dependent fashion. Mild (1 sciatic constriction) and classic (4 sciatic constrictions) CCI was performed on male Sprague Dawley (SD) and Fischer 344 (F344) rats, respectively. Beginning 10–14 days after CCI surgery, s.c. morphine (5 mg/kg or equivolume saline b.i.d.) was administered for 5 consecutive days. This morphine protocol potentiated the magnitude of mild CCI-induced allodynia (von Frey test) in SD rats ( n = 10/group; p < 0.05), and prolonged the duration of classic CCI-induced allodynia in F344 rats ( n = 6/group; p < 0.05). The TLR4 antagonist (+)-naloxone was co-administered with morphine treatment via intrathecal osmotic minipump (60 μg/h), which completely abolished potentiated allodynia in SD rats ( n = 6/group; p < 0.05). A single intrathecal dose of interleukin-1 (IL-1) receptor antagonist (100 μg; Amgen) transiently restored thresholds to pre-surgery levels ( n = 4/group; p < 0.05). An interaction between CCI and morphine was present for GFAP expression at 21 days after the conclusion of morphine administration in SD rats ( n = 4/group; p < 0.01). These data indicate that morphine potentiation of allodynia is dependent on TLR4 and IL-1 signaling in the CNS, and that morphine and the products of nerve injury may interact, resulting in paradoxical enhancement of neuropathic pain.