Inhibition of enkephalin metabolism and activation of mu- or delta-opioid receptors elicit opposite effects on reward and motility in the ventral mesencephalon

Heidbreder, Christian; Gewiss, M.; Lallemand, S.; Roques, B. P.; Witte, Philippe De

doi:10.1016/0028-3908(92)90179-s

Cited by 7 publications

(1 citation statement)

References 22 publications

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“…Godfrey et al [ 71 ] developed a chitosan-based nanoparticle formulation for intranasal delivery of native ENK and showed strong antinociception without inducing tolerance or hyperactivity after repeated administrations. Similarly, dual enkephalinase inhibitors, which increase the extracellular level of ENKs were shown to produce antinociception without respiratory disturbance, constipation, analgesic tolerance, addiction, or dependence in several animal models [ 64 , 65 , 66 , 67 , 70 , 73 , 74 , 75 ].…”

Section: Resultsmentioning

confidence: 99%

An Effective and Safe Enkephalin Analog for Antinociception

et al. 2021

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Opioids account for 69,000 overdose deaths per annum worldwide and cause serious side effects. Safer analgesics are urgently needed. The endogenous opioid peptide Leu-Enkephalin (Leu-ENK) is ineffective when introduced peripherally due to poor stability and limited membrane permeability. We developed a focused library of Leu-ENK analogs containing small hydrophobic modifications. N-pivaloyl analog KK-103 showed the highest binding affinity to the delta opioid receptor (68% relative to Leu-ENK) and an extended plasma half-life of 37 h. In the murine hot-plate model, subcutaneous KK-103 showed 10-fold improved anticonception (142%MPE·h) compared to Leu-ENK (14%MPE·h). In the formalin model, KK-103 reduced the licking and biting time to ~50% relative to the vehicle group. KK-103 was shown to act through the opioid receptors in the central nervous system. In contrast to morphine, KK-103 was longer-lasting and did not induce breathing depression, physical dependence, and tolerance, showing potential as a safe and effective analgesic.

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