TRPC1/4/5 channels contribute to morphine‐induced analgesic tolerance and hyperalgesia by enhancing spinal synaptic potentiation and structural plasticity

Abstract

Opioid analgesics remain the mainstay for managing intractable chronic pain, but their use is limited by detrimental side effects such as analgesic tolerance and hyperalgesia. Calcium‐dependent synaptic plasticity is a key determinant in opiates tolerance and hyperalgesia. However, the exact substrates for this calcium‐dependent synaptic plasticity in mediating these maladaptive processes are largely unknown. Canonical transient receptor potential 1, 4, and 5 (TRPC1, 4, 5) proteins assemble into heteromultimeric nonselective cation channels with high Ca2+ permeability and influence various neuronal functions. However, whether and how TRPC1/4/5 channels contribute to the development of opiates tolerance and hyperalgesia remains elusive. Here, we show that TRPC1/4/5 channels contribute to the generation of morphine tolerance and hyperalgesia. Chronic morphine exposure leads to upregulation of TRPC1/4/5 channels in the spinal cord. Spinally expressed TRPC1, TPRC4, and TRPC5 are required for chronic morphine‐induced synaptic long‐term potentiation (LTP) as well as remodeling of synaptic spines in the dorsal horn, thereby orchestrating functional and structural plasticity during the course of morphine‐induced hyperalgesia and tolerance. These effects are attributed to TRPC1/4/5‐mediated Ca2+ elevation in the spinal dorsal horn induced by chronic morphine treatment. This study identifies TRPC1/4/5 channels as a promising novel target to prevent the unwanted morphine tolerance and hyperalgesia.

Spinal TRPA1 Contributes to the Mechanical Hypersensitivity Effect Induced by Netrin-1

“…Although our present results do not support the hypothesis that spinal TRPC4/C5 had a key role in mediating the hypersensitivity effect induced by netrin-1, this proposal does not exclude the potential pronociceptive role of spinal TRPC4/C5 in other conditions. In line with this caveat, a recent study reported that morphine-induced analgesic tolerance and hyperalgesia were associated with increased expression of spinal TRPC4/C5 [ 32 ].…”

Canonical Transient Receptor Potential Channels as Novel Targets for Antiepileptic Drugs

“…If one infers from the existence of a negative slope region in mGluR1/5-induced current, heteromeric TRPC1/5 could be abundant in CA3 pyramidal neurons. Heteromeric channels comprised of all three members of the TRPC1/4/5 subgroup may also exist in some neurons (85).…”

Heteromeric TRP Channels in Lung Inflammation

“…Heteromeric assemblies of TRP channel subunits are known to be formed within their subfamily and moreover with TRP channel subunits from other subfamilies, as it has been demonstrated for heteromeric assemblies of TRPP2/C1 in pig kidney epithelial cells [ 21 ], or TRPC1/V6 and TRPML/V5 in HEK293 cells [ 60 , 61 ]. Heteromerization of three different TRP channel subunits has also been described, e.g., for TRPC3/C6/C7 [ 62 ], TRPC1/C4/C5 [ 63 ], or TRPV4/C1/P2 [ 64 ] although heteromerization of two TRP channel subunits seems to be more commonly found [ 20 ]. It seems fair to speculate that with an increasing number of different TRP channel subunits being co-expressed in the same tissue or cell type, the probability for heteromerization increases which in turn may serve as a mechanism to fine-tune cellular responses to tissue-specific environmental stimuli [ 65 ].…”