Abstract
Author SummaryPain is an important physiological function that protects our body from harm. Pain-sensing neurons, called nociceptors, transduce harmful stimuli into electrical signals and transmit this information to the brain via the spinal cord. When nociceptors are persistently activated, such as after injury, the connections they make with neurons in the spinal cord are altered in a process called synaptic long-term potentiation (LTP). In this study, we examine the molecular and cellular mechanisms of LTP at synapses from nociceptors onto spinal neurons. We use multiple experimental approaches in mice, from genetic to behavioural, to show that this form of LTP involves presynaptic events that unfold in nociceptors when they are repetitively activated. In particular, an enzyme activated by the second messenger cGMP, referred to as Protein Kinase G-I, phosphorylates presynaptic proteins and increases the release of neurotransmitters from nociceptor endings in the spinal cord. When we genetically silence Protein Kinase G-I or block its activation in nociceptors, inflammatory pain is markedly reduced at the behavioural level. These results clarify basic mechanisms of pathological pain and pave the way for new therapeutic approaches.
Highlights
Plasticity in peripheral nociceptors and their synapses with spinal neurons has been proposed as a cellular basis for the development and maintenance of pain hypersensitivity following peripheral inflammation or nerve injury [1,2,3]
Large-diameter neurofilament-200-immunoreactive neurons entirely retained Protein Kinase G1 (PKG-I) expression in the SNS-PKG-I2/2 mice (Figure 1C,D). These results show that PKG-I is normally expressed in most nociceptors and is selectively lost from these neurons, but not from tactile-responsive and proprioceptive dorsal root ganglia (DRG) neurons, in SNS-PKG-I2/2 mice
Our results indicate that this function is mediated by cGMP acting via PKG-I
Summary
Plasticity in peripheral nociceptors and their synapses with spinal neurons has been proposed as a cellular basis for the development and maintenance of pain hypersensitivity following peripheral inflammation or nerve injury [1,2,3]. Activation of nociceptive nerve afferents at frequencies relevant to pathological pain states can trigger long-term potentiation (LTP) at spinal synapses between nociceptor terminals and spinal neurons projecting nociceptive information to the brain [4,5]. When nociceptors are persistently activated, such as after injury, the connections they make with neurons in the spinal cord are altered in a process called synaptic long-term potentiation (LTP). When we genetically silence Protein Kinase G-I or block its activation in nociceptors, inflammatory pain is markedly reduced at the behavioural level. These results clarify basic mechanisms of pathological pain and pave the way for new therapeutic approaches
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