Studies on spinal opiate receptor pharmacology. III. Analgetic effects of enkephalin dimers as measured by cutaneous-thermal and visceral-chemical evoked responses.

Abstract d -Ala 2 - d -Leu 5 -enkephalin (DADL) along with dimers formed from tetra(DTE: des-Leu 5 -enkephalin)- or pentapeptide (DPE: Leu 5 -enkephalin) coupled by methylene bridges of various lengths (n) have been shown in vitro systems to possess varying degrees of μ/δ-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 δ-receptor selectivity were active in the TF(DPE 2 ≥DADL≥DTE 2 ≥morphine>DPE 12 ⋙DTE 12 = 0) and HP(DPE 2 ≥DTE 2 ≥DADL≥morphine>DPE 12 ≥DTE 12 > 0. To examine cross-tolerance, the intrathecal ED 50 for morphine, DPE and DADL were determined in rats rendered tolerant by subcutaneous morphine pellets. The TF ED 50 tolerant/TF ED 50 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 × TF ED 50 ), morphine produced a motor rigidity which blocked the placing and stepping reflex. In contrast, injection of DADL and the more active dimers resulted in a waxy flaccidity at doses around 15–60 times the TF ED 50 . These observations together offer strong support for a functional separation of two classes of spinal receptors which modulate the animal's response to distinguishable noxious stimuli.