Studies on spinal opiate receptor pharmacology. III. Analgetic effects of enkephalin dimers as measured by cutaneous-thermal and visceral-chemical evoked responses.
D-Ala2-D-Leu5-enkephalin (DADL) along with dimers formed from tetra(DTE: des-Leu5-enkephalin)- or pentapeptide (DPE: Leu5-enkephalin) coupled by methylene bridges of various lengths (n) have been shown in in vitro systems to possess varying degrees of mu/delta-receptor selectivity. In the present studies we have systematically compared the intrathecal effect of these agents and morphine on the cutaneous stimuli (hot plate (HP) and tail flick (TF) and visceral-chemical (writhing) tests in the rat. The following observations were made. (1) Dimers with high delta-receptor selectivity were active in the TF(DPE2 greater than or equal to DADL greater than or equal to DTE2 greater than or equal to morphine greater than DPE12 much greater than DTE12 = 0) and HP(DPE2 greater than or equal to DTE2 greater than or equal to DADL greater than or equal to morphine greater than DPE12 greater than or equal to DTE12 greater than 0. To examine cross-tolerance, the intrathecal ED50 for morphine, DPE and DADL were determined in rats rendered tolerant by subcutaneous morphine pellets. The TF ED50 tolerant/TF ED50 naive was 18.4, 5.4 and 1.3, respectively. The ratio of activity on the HP was 14.0, 4.7 and 2.2 (2) On the visceral-chemical test, only morphine was active. The dimers or DADL in doses which totally blocked the TF or HP are at higher doses which were just below those producing motor dysfunction had no effect on the writhing response. (3) At high intrathecal doses (40 X TF ED50), morphine produced a motor rigidity which blocked the placing and stepping reflex.(ABSTRACT TRUNCATED AT 250 WORDS)
Schmauss
C
C
Shimohigashi
Y
Y
Jensen
T S
TS
Rodbard
D
D
Yaksh
T L
TL
D000085:Acetates; D019342:Acetic Acid; D000700:Analgesics; D000818:Animals; D004743:Enkephalin, Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D016308:Enkephalin, Leucine-2-Alanine; D004745:Enkephalins / Q000494:pharmacology*; D006358:Hot Temperature / Q000009:adverse effects; D008297:Male; D009020:Morphine / Q000627:therapeutic use; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy*; D051381:Rats; D011919:Rats, Inbred Strains; D011957:Receptors, Opioid / Q000187:drug effects*; D012867:Skin / Q000294:innervation; D013116:Spinal Cord / Q000187:drug effects*
D000085:Acetates; D000700:Analgesics; D004745:Enkephalins; D011957:Receptors, Opioid; D004743:Enkephalin, Leucine; D016308:Enkephalin, Leucine-2-Alanine; D009020:Morphine; D019342:Acetic Acid