Analgesic Effects Of Spinal Endomorphine On Peripheral Inflammation--Behavioral Study

Superficial layers of spinal dorsal horn receive not only nociception from primary afferent input, but also inhibitory information from projective fiber in local endogenous analgesic system. Opioids in superficial layer of spinal dorsal horn effectively modulate nociception from peripheral site. There are densely endomorphines (EMs) -like immunoreactive fibers and terminals in the superficial layer. EMs are highly affinity endogenous ligands to mu-opioid receptor (MOR). Their distribution patterns match to MOR in spinal dorsal horn. EMs include EMI and EM2; in rodents EMI exists mainly in superspinal structures and EM2 is mainly located in the spinal cord. EM2 in spinal dorsal horn mostly originate from primary afferent fiber. EMs exert stronger analgesic effects via intrathecal (i.t.) than i.c.v.. Electrophysiological study indicated that i.t. EM2 selectively inhibited nociception evoked bystimulation of C-fiber. There are a large of EM2-like immunoreactive neurons in dorsal root ganglia (DRG). These indicate that EMs play important roles in modulatory of nociception. To explore analgesic mechanism of EMs, in the present study we investigated effects of EMs under tissue inflammatory state induced by subcutaneous complete Fruends' Adjuvant (CFA) using behavioral study.Results:1. Effects of pre-treatment EMs via i.t. on primary mechanical allodynia and thermal hyperalgesia induced by s.c. CFA(1) Pre-treatment with i.t. EM2 (0.02, 0.2, 2, 20 μg / 10 μ1) could dose-dependent inhibit s.c. CFA induced primary mechanical allodynia, but not thermal hyperalgesia.(2) Pre-treatment with i.t. EMI (20 μg /10 μl) had no effects on both primary mechanical allodynia and thermal hyperalgesia induced by s.c. CFA.2. Effects of non-selective antagonist of tachykinin receptors spantide and its interaction with EM2 on primary mechanical allodynia and thermal hyperalgesia induced by s.c. CFA(1) Pre-treatment with i.t non-selective antagonist of neurokinin (NK) receptor spantide could dose-dependent reverse primary mechanical allodynia and thermal hyperalgesia induced by s.c. CFA, but had no effect on thermal hyperalgesia.(2) Pre-treatment with i.t. both EM2 and spantide could synergicly inhibit primary mechanical allodynia induced by s.c. CFA.3. Effects of pre-treatment with i.t. NK selective antagonists or co-administered with EM2 on primary mechanical allodynia and thermal hyperalgesia induced by s.c. CFA(1) Pre-treatment with i.t. NK₁ specific antagonist L-732138 could dose-dependent inhibit primary mechanical allodynia, but not thermal hyperalgesia induced by s.c. CFA.(2) Pre-treatments separately with i.t. NK₂ and NK3 selective antagonists GR94800 and SR142801 had no effects on both primary mechanical allodynia and thermal hyperalgesia.(3) Co-administered EM2 and L-732138 could largely inhibit primary mechanical allodynia induced by s.c. CFA, and their inhibitory effects are synergic.4. Effects of i.t. substance P (SP) and co-administered with EMs on primary mechanical allodynia and thermal hyperalgesia induced by s.c. CFA.(1) Pre-treatment with SP could enhance primary mechanical allodynia, but no effect on thermal hyperalgesia induced by s.c. CFA.(2) Pre-coadministered i.t. SP and EM2 could reverse the inhibitory effect of EM2 on primary mechanical allodynia induced by s.c. CFA.5. Effects of spinal EMs on mirror-image pain induced by s.c. CFA injection into one hindpaw(1) S.c. injection of CFA into one hindpaw could induce mechanical allodynia at mirror-image side 1-24 h after injection. 4-16 h after injection are peak time of mirror-image pain.(2) Pre-treatment with i.t. EM2 (0.02, 0.2,2, 20μg / 10μl), but not EMI (20μg...