TY - JOUR
T1 - Opioid-induced hyperalgesia and tolerance are driven by HCN ion channels
T2 - Opioid addiction and HCN ion channels
AU - McNaughton, Peter
AU - Han, Xue
AU - Garcia Pinto, Larissa
AU - Vilar, Bruno
N1 - Funding Information:
We thank Carl Hobbs for assisting with immunohistochemistry, Alice Fuller for carrying out the blinding process in behavioral assays, and Chris Tsantoulas for comments on the MS. This work was supported by grants from the Wellcome Trust to P.A.M (Investigator Award 205006/Z/16/Z) and a China Scholarship Council (CSC) PhD studentship award to X.H. X.H. and P.A.M. planned the study and wrote the manuscript. X.H. performed behavioral experiments, patch-clamping, immunohistochemistry, ELISA, and qPCR. L.G.P. performed qPCR and ELISA.
Publisher Copyright:
Copyright © 2024 the authors.
PY - 2024/2/4
Y1 - 2024/2/4
N2 - Prolonged exposure to opioids causes an enhanced sensitivity to painful stimuli (opioid-induced hyperalgesia, OIH) and a need for increased opioid doses to maintain analgesia (opioid-induced tolerance, OIT), but the mechanisms underlying both processes remain obscure. We found that pharmacological block or genetic deletion of HCN2 ion channels in primary nociceptive neurons of male mice completely abolished OIH but had no effect on OIT. Conversely, pharmacological inhibition of central HCN channels alleviated OIT but had no effect on OIH. Expression of C-FOS, a marker of neuronal activity, was increased in second-order neurons of the dorsal spinal cord by induction of OIH, and the increase was prevented by peripheral block or genetic deletion of HCN2, but block of OIT by spinal block of HCN channels had no impact on C-FOS expression in dorsal horn neurons. Collectively, these observations show that OIH is driven by HCN2 ion channels in peripheral nociceptors, while OIT is driven by a member of the HCN family located in the CNS. Induction of OIH increased cAMP in nociceptive neurons, and a consequent shift in the activation curve of HCN2 caused an increase in nociceptor firing. The shift in HCN2 was caused by expression of a constitutively active μ-opioid receptor (MOR) and was reversed by MOR antagonists. We identified the opioid-induced MOR as a six-transmembrane splice variant, and we show that it increases cAMP by coupling constitutively to G
s. HCN2 ion channels therefore drive OIH, and likely OIT, and may be a novel therapeutic target for the treatment of addiction.
AB - Prolonged exposure to opioids causes an enhanced sensitivity to painful stimuli (opioid-induced hyperalgesia, OIH) and a need for increased opioid doses to maintain analgesia (opioid-induced tolerance, OIT), but the mechanisms underlying both processes remain obscure. We found that pharmacological block or genetic deletion of HCN2 ion channels in primary nociceptive neurons of male mice completely abolished OIH but had no effect on OIT. Conversely, pharmacological inhibition of central HCN channels alleviated OIT but had no effect on OIH. Expression of C-FOS, a marker of neuronal activity, was increased in second-order neurons of the dorsal spinal cord by induction of OIH, and the increase was prevented by peripheral block or genetic deletion of HCN2, but block of OIT by spinal block of HCN channels had no impact on C-FOS expression in dorsal horn neurons. Collectively, these observations show that OIH is driven by HCN2 ion channels in peripheral nociceptors, while OIT is driven by a member of the HCN family located in the CNS. Induction of OIH increased cAMP in nociceptive neurons, and a consequent shift in the activation curve of HCN2 caused an increase in nociceptor firing. The shift in HCN2 was caused by expression of a constitutively active μ-opioid receptor (MOR) and was reversed by MOR antagonists. We identified the opioid-induced MOR as a six-transmembrane splice variant, and we show that it increases cAMP by coupling constitutively to G
s. HCN2 ion channels therefore drive OIH, and likely OIT, and may be a novel therapeutic target for the treatment of addiction.
UR - http://www.scopus.com/inward/record.url?scp=85184617315&partnerID=8YFLogxK
U2 - 10.1523/JNEUROSCI.1368-23.2023
DO - 10.1523/JNEUROSCI.1368-23.2023
M3 - Article
SN - 0270-6474
VL - 44
SP - 1
EP - 63
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 6
M1 - e1368232023
ER -
