Signaling pathways and ion channels in osteoarthritis: a review of recent advances.

Recent evidence indicates that opioid and cannabinoid receptors may interact functionally within the central nervous system (CNS). These interactions can occur directly, such as through receptor heteromerization, or indirectly via signaling convergence, in which activation of one system influences endogenous ligand release or downstream signaling in another. Such receptor interplay may underlie various behavioral effects associated with drug use, including acute antinociception []. The opioid receptor system includes three main subtypes—mu (MOR), delta (DOR), and kappa (KOR)—which are activated by endogenous peptides such as β-endorphin, enkephalin, and dynorphin []. In parallel, the endocannabinoid system (ECS) consists of two classical cannabinoid receptors (CB1Rs and CB2Rs), endogenous cannabinoids (eCBs), and the enzymes that synthesize and degrade them. The discovery of additional lipid mediators, enzymes, and receptors has broadened this system into what is now termed the endocannabinoidome (eCBome) []. CB2Rs are predominantly expressed in peripheral tissues, particularly within organs involved in immune function [, ]. They are also present in central nervous system cells, including microglia and neurons in the hippocampus, striatum, and brainstem []. Although the functional presence of CB2Rs in neurons has been debated, mounting evidence—including our own research—has confirmed their expression and regulatory role in response to drugs of abuse [–]. Opioid and cannabinoid receptors share similar signaling characteristics. As G protein-coupled receptors (GPCRs), they inhibit cyclic AMP production via Giα coupling, activate MAP kinase pathways through secondary messengers, and suppress neurotransmitter release by inhibiting calcium influx and promoting potassium efflux [, ]. Opioid and cannabinoid receptors share similar Gi-coupled signaling properties, and their effects may converge at the level of intracellular pathways or neuroimmune modulation; however, the present study does not test direct receptor–receptor interactions []. There is growing evidence that the opioid and endocannabinoid systems interact across molecular and behavioral domains, influencing processes such as pain perception, reward mechanisms, and addiction susceptibility [, ]. Recognizing this interplay may inform the development of novel therapeutics with reduced risk of abuse. Strategically targeting both systems holds promise for advancing treatment approaches for pain and substance use disorders. In behavioral studies involving mice, the endocannabinoid system—particularly CB2Rs—has been implicated in regulating inflammation and motor activity. CB2Rs primarily exert their effects through immune cells and CNS microglia. Their activation has been shown to lower pro-inflammatory cytokine levels and limit immune cell infiltration into affected tissues [, ] These receptors also modulate neuroinflammation-related motor function. For instance, in a Parkinson’s disease model, CB2R activation reduced alpha-synuclein aggregation and protected dopaminergic neurons in the substantia nigra, indicating a neuroprotective capacity [].