Bifunctional μ opioid and σ₁ receptor ligands as novel analgesics with reduced side effects

Opioid analgesics are highly effective painkillers for the treatment of moderate or severe pain, but they are associated with a number of undesirable adverse effects, including the development of tolerance, addiction, constipation and life-threatening respiratory depression. The development of new and safer analgesics with innovative mechanisms of action, which can enhance the efficacy in comparison to available treatments and reduce their side effects, is urgently needed. The sigma-1 receptor (σ₁R), a unique Ca²⁺-sensing chaperone protein, is expressed throughout pain-modulating tissues and affects neurotransmission by interacting with different protein partners, including molecular targets that participate in nociceptive signalling, such as the μ-opioid receptor (MOR), N-methyl-d-aspartate receptor (NMDAR) and cannabinoid 1 receptor (CB₁R). Overwhelming pharmacological and genetic evidence indicates that σ₁R antagonists induce anti-hypersensitive effects in sensitising pain conditions (e.g. chemically induced, inflammatory and neuropathic pain) and enhance opioid analgesia but not opioid-mediated detrimental effects. It has been suggested that balanced modulation of MORs and σ₁Rs may improve both the therapeutic efficacy and safety of opioids. This review summarises the functional profiles of ligands with mixed MOR agonist and σ₁R antagonist activities and highlights their therapeutic potentials for pain management. Dual MOR agonism/σ₁R antagonism represents a promising avenue for the development of potent and safer analgesics.