Orally Active Peptide Vector Allows Using Cannabis to Fight Pain While Avoiding Side Effects

[Image: see text] The activation of cannabinoid CB(1) receptors (CB(1)R) by Δ(9)-tetrahydrocannabinol (THC), the main component of Cannabis sativa, induces analgesia. CB(1)R activation, however, also causes cognitive impairment via the serotonin 5HT(2A) receptor (5HT(2A)R), a component of a CB(1)R–5HT(2A)R heteromer, posing a serious drawback for cannabinoid therapeutic use. We have shown that peptides reproducing CB(1)R transmembrane (TM) helices 5 and 6, fused to a cell-penetrating sequence (CPP), can alter the structure of the CB(1)R–5HT(2A)R heteromer and avert THC cognitive impairment while preserving analgesia. Here, we report the optimization of these prototypes into drug-like leads by (i) shortening the TM5, TM6, and CPP sequences, without losing the ability to disturb the CB(1)R–5HT(2A)R heteromer, and (ii) extensive sequence remodeling to achieve protease resistance and blood–brain barrier penetration. Our efforts have culminated in the identification of an ideal candidate for cannabis-based pain management, an orally active 16-residue peptide preserving THC-induced analgesia.