The mechanism of μ-opioid receptor (MOR)-TRPV1 crosstalk in TRPV1 activation involves morphine anti-nociception, tolerance and dependence

Abstract

Initiated by the activation of various nociceptors, pain is a reaction to specific stimulus modalities. The μ-opioid receptor (MOR) agonists, including morphine, remain the most potent analgesics to treat patients with moderate to severe pain. However, the utility of MOR agonists is limited by the adverse effects associated with the use of these drugs, including analgesic tolerance and physical dependence. A strong connection has been suggested between the expression of the transient receptor potential vanilloid type 1 (TRPV1) ion channel and the development of inflammatory hyperalgesia. TRPV1 is important for thermal nociception induction, and is mainly expressed on sensory neurons. Recent reports suggest that opioid or TRPV1 receptor agonist exposure has contrasting consequences for anti-nociception, tolerance and dependence. Chronic morphine exposure modulates TRPV1 activation and induces the anti-nociception effects of morphine. The regulation of many downstream targets of TRPV1 plays a critical role in this process, including calcitonin gene-related peptide (CGRP) and substance P (SP). Additional factors also include capsaicin treatment blocking the anti-nociception effects of morphine in rats, as well as opioid modulation of TRPV1 responses through the cAMP-dependent PKA pathway and MAPK signaling pathways. Here, we review new insights concerning the mechanism underlying MOR-TRPV1 crosstalk and signaling pathways and discuss the potential mechanisms of morphine-induced anti-nociception, tolerance and dependence associated with the TRPV1 signaling pathway and highlight how understanding these mechanisms might help find therapeutic targets for the treatment of morphine induced antinociception, tolerance and dependence.

Keywords: calcitonin gene-related peptide (CGRP); ion channel; opioid tolerance; substance P (SP); transient receptor potential vanilloid type 1 (TRPV1); μ opioid receptor (MOR).

Figure 1.

Signal transduction of TRPV1 activation in morphine induced antinociception, tolerance and dependence. By acting on μ- opioid receptors (MOR), primarily through G_ai-subunits, morphine reduces adenylyl cyclase (AC) activity. AC catalyzes the conversion of adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP), which regulates protein kinase A (PKA) or cyclic-nucleotide-gated ion channels. TRPV1 activation results in sensitization of TRPV1 responses through a β- arrestin2 and PKA-dependent manner. Decreased association of β-arrestin2 and constitutive phosphorylation of TRPV1 may underlie enhanced pain perception and hyperalgesia. Chronic administration of morphine activates the MAPK pathway, including ERK, p38 and JNK. This possibly occurs via protein kinase A (PKA), protein kinase C (PKC) and phosphatidylinositol 3-kinase (PI3K). The nuclear translocation of phosphorylated MAPK results in the phosphorylation of transcription factors, such as CREB and c-Jun. This leads to TRPV1 activation through modulation of neurotransmitters such as glutamate, CGRP and SP released from DRG neurons and further contributes to the antinociception, tolerance and dependence associated thermal hyperalgesia.