TY - JOUR
T1 - An investigation into the noradrenergic and serotonergic contributions of diffuse noxious inhibitory controls in a monoiodoacetate model of osteoarthritis
AU - Lockwood, S. M.
AU - Bannister, K.
AU - Dickenson, A. H.
PY - 2019/1/1
Y1 - 2019/1/1
N2 - Osteoarthritis (OA) is a debilitating conditioning with pain as the major clinical symptom. Understanding the mechanisms that drive OA-associated chronic pain is crucial for developing the most effective analgesics. Although the degradation of the joint is the initial trigger for the development of chronic pain, the discordance between radiographic joint damage and the reported pain experience in patients, coupled with clinical features that cannot be explained by purely peripheral mechanisms, suggest there are often other factors at play. Therefore, this study considers the central contributions of chronic pain, using a monoiodoacetate (MIA) model of OA. Particularly, this study explores the functionality of descending controls over the course of the model by assessing diffuse noxious inhibitory controls (DNIC). Early-phase MIA animals have a functional DNIC system, whereas DNIC are abolished in late-phase MIA animals, indicating a dysregulation in descending modulation over the course of the model. In early-phase animals, blocking the actions of spinal δ2-adrenergic receptors completely abolishes DNIC, whereas blocking the actions of spinal 5-HT7 receptors only partially decreases the magnitude of DNIC. However, activating the spinal δ2-adrenergic or 5-HT7 receptors in late-phase MIA animals restored DNIC-induced neuronal inhibition. This study confirms that descending noradrenergic signaling is crucial for DNIC expression. Furthermore, we suggest a compensatory increase in descending serotonergic inhibition acting at 5-HT7 receptors as the model progresses such that receptor activation is sufficient to override the imbalance in descending controls and mediate neuronal inhibition. NEW & NOTEWORTHY This study showed that there are both noradrenergic and serotonergic components contributing to the expression of diffuse noxious inhibitory controls (DNIC). Furthermore, although a tonic descending noradrenergic tone is always crucial for the expression of DNIC, variations in descending serotonergic signaling over the course of the model mean this component plays a more vital role in states of sensitization.
AB - Osteoarthritis (OA) is a debilitating conditioning with pain as the major clinical symptom. Understanding the mechanisms that drive OA-associated chronic pain is crucial for developing the most effective analgesics. Although the degradation of the joint is the initial trigger for the development of chronic pain, the discordance between radiographic joint damage and the reported pain experience in patients, coupled with clinical features that cannot be explained by purely peripheral mechanisms, suggest there are often other factors at play. Therefore, this study considers the central contributions of chronic pain, using a monoiodoacetate (MIA) model of OA. Particularly, this study explores the functionality of descending controls over the course of the model by assessing diffuse noxious inhibitory controls (DNIC). Early-phase MIA animals have a functional DNIC system, whereas DNIC are abolished in late-phase MIA animals, indicating a dysregulation in descending modulation over the course of the model. In early-phase animals, blocking the actions of spinal δ2-adrenergic receptors completely abolishes DNIC, whereas blocking the actions of spinal 5-HT7 receptors only partially decreases the magnitude of DNIC. However, activating the spinal δ2-adrenergic or 5-HT7 receptors in late-phase MIA animals restored DNIC-induced neuronal inhibition. This study confirms that descending noradrenergic signaling is crucial for DNIC expression. Furthermore, we suggest a compensatory increase in descending serotonergic inhibition acting at 5-HT7 receptors as the model progresses such that receptor activation is sufficient to override the imbalance in descending controls and mediate neuronal inhibition. NEW & NOTEWORTHY This study showed that there are both noradrenergic and serotonergic components contributing to the expression of diffuse noxious inhibitory controls (DNIC). Furthermore, although a tonic descending noradrenergic tone is always crucial for the expression of DNIC, variations in descending serotonergic signaling over the course of the model mean this component plays a more vital role in states of sensitization.
KW - Descending modulation
KW - Diffuse noxious inhibitory controls
KW - Norepinephrine
KW - Serotonin
UR - http://www.scopus.com/inward/record.url?scp=85059190465&partnerID=8YFLogxK
U2 - 10.1152/jn.00613.2018
DO - 10.1152/jn.00613.2018
M3 - Article
C2 - 30461363
AN - SCOPUS:85059190465
SN - 0022-3077
VL - 121
SP - 96
EP - 104
JO - Journal of Neurophysiology
JF - Journal of Neurophysiology
IS - 1
ER -