Alterations of pain modulation following neuropathic pain and their implications for brain function and analgesic efficacy

Chronic pain leads to anatomical and functional alterations in the spinal cord and brain in both animals and humans. The changes in the spinal cord represent a form of central sensitization that can worsen pain. Chronic pain is also associated with cognitive deficits due to brain dysfunction. The mechanisms underlying these symptoms, however, have not yet been fully elucidated. In the early phase after peripheral nerve injury, spinal noradrenergic and cholinergic tone increases, thereby enhancing inhibitory signaling. These signals diminish over time, however, along with the loss of stimulus–evoked activation of the locus coeruleus. In the later phase, animals with neuropathic pain exhibit reduced endogenous analgesia mediated by both noradrenergic and cholinergic pathways. These changes impair the resolution of acute pain, reduce analgesic drug efficacy for neuropathic pain, and impair noradrenaline–mediated brain function. Nerve injury also alters cholinergic, gamma–aminobutyric acid, and dopaminergic systems in the brain, contributing to impaired brain function. Spontaneously hypertensive rats and 6–hydroxydopamine–treated mice exhibit attention deficit hyperactivity disorder (ADHD)–like behaviors and altered pain modulation due to changes in the noradrenergic or dopaminergic systems, even in the absence of nerve injury. A link between ADHD and chronic pain has also been observed in humans, suggesting that shared neurological mechanisms underlie both conditions. This review presents experimental findings of spinal and brain alterations in the chronic neuropathic pain model. Comprehensive investigations to elucidate the reciprocal interactions are crucial for developing effective treatments and preventive strategies for chronic pain and its associated symptoms.