From the Guidelines
Pain processing in the nervous system is a multidimensional phenomenon that involves the detection of noxious stimuli by nociceptors, transmission of signals to the spinal cord and brain, and modulation by descending pathways and neurotransmitters, as recently outlined in the British Journal of Pharmacology 1. The process begins with the detection of harmful stimuli by nociceptors, which can be triggered by a wide variety of thermal, chemical, mechanical, and inflammatory stimuli, leading to the activation of C and Aδ fibres that convey nociceptive stimuli to the dorsal horn of the spinal cord 1.
- Key players in this process include:
- Inflammatory mediators, such as monoamines, cytokines, prostanoids, and peptides
- Neurotransmitters, including glutamate, substance P, and CGRP
- Adenosine triphosphate (ATP), nitric oxide (NO), and neurotrophins
- At the spinal dorsal horn, excitatory amino acids (EAAs) and neuropeptides synergistically elicit excitatory postsynaptic potentials, and nociceptive stimuli are transmitted through ascending pathways to thalamic, limbic, and cortical structures responsible for discriminative responses 1. The modulation of pain signals is crucial, with inhibitory interneurons playing an important role in limiting the flow of nociceptive information to supraspinal areas, and descending pathways originating in the brainstem and other cerebral structures regulating the nociceptive information at the spinal dorsal horn 1.
- Key neurotransmitters involved in this modulation include:
- 5-hydroxtryptamine (5-HT, serotonin)
- Noradrenaline
- Dopamine The complex interplay between these factors and pathways allows for the conscious experience of pain, which can be influenced by biological, psychological, and social factors, as defined by the International Association for the Study of Pain (IASP) 1.
From the FDA Drug Label
Although the mechanism of action of pregabalin has not been fully elucidated, results with genetically modified mice and with compounds structurally related to pregabalin (such as gabapentin) suggest that binding to the alpha2-delta subunit may be involved in pregabalin's anti-nociceptive and antiseizure effects in animals In animal models of nerve damage, pregabalin has been shown to reduce calcium-dependent release of pro-nociceptive neurotransmitters in the spinal cord, possibly by disrupting alpha2-delta containing-calcium channel trafficking and/or reducing calcium currents Evidence from other animal models of nerve damage and persistent pain suggest the anti-nociceptive activities of pregabalin may also be mediated through interactions with descending noradrenergic and serotonergic pathways originating from the brainstem that modulate pain transmission in the spinal cord
The nervous system processes pain through the following mechanisms:
- Calcium-dependent release of pro-nociceptive neurotransmitters in the spinal cord
- Descending noradrenergic and serotonergic pathways originating from the brainstem that modulate pain transmission in the spinal cord
- Binding to the alpha2-delta subunit of voltage-gated calcium channels in central nervous system tissues, which may be involved in the anti-nociceptive effects of pregabalin 2
From the Research
Nervous System Processing of Pain
The nervous system processes pain through a complex interplay of messages sent from the periphery to the central nervous system and vice versa, involving specific pathways that carry and modulate pain information 3.
- Pain Pathways: There are several pathways that transmit information about pain from the periphery to the brain, including the spinothalamic tract and the dorsal column-medial lemniscus pathway 4.
- Modulatory Signals: A network of pathways carries modulatory signals from the brain and brainstem that alter the incoming flow of pain information, allowing for the regulation of pain perception 4.
- Nociceptors: Nociceptors are sensory receptors that are activated by noxious stimuli that damage or threaten the body's integrity, and are classified according to their responses to mechanical, thermal, and chemical stimuli 5.
- Nociceptor Classification: Nociceptors can be classified into different types, including high-threshold mechano-nociceptors (HTMs) and mechano-heat nociceptors of A and C fibres (AMHs and CMHs), which are found in the skin and deep tissues 5.
Pain Processing Mechanisms
The processing of pain involves the activation of nociceptors, which transmit signals to the spinal cord and brain, where they are interpreted as pain 6.
- Nociceptor Activation: Nociceptors can be activated by various stimuli, including mechanical, thermal, and chemical stimuli, and can be sensitized by inflammatory mediators such as capsaicin, bradykinin, and prostaglandins 5.
- Signal Transmission: The signals transmitted by nociceptors are processed in the spinal cord and brain, where they are modulated by various mechanisms, including inhibition and facilitation 4.
- Pain Perception: The perception of pain is a complex process that involves the integration of multiple signals and pathways, and can be influenced by various factors, including emotional state, attention, and past experiences 3.
Treatment of Pain
The treatment of pain often involves the use of pharmacological agents that target specific components of the pain pathway, including nociceptive and neuropathic pain components 7.
- Pharmacological Management: Pharmacological management of chronic low back pain (LBP) may involve the use of agents such as paracetamol, non-steroidal anti-inflammatory drugs, and cyclo-oxygenase-2 inhibitors, which target the nociceptive component of pain 7.
- Targeting Nociceptive and Neuropathic Pain: Antidepressants and opioids may be used to target the neuropathic component of pain, while agents such as lidocaine and pregabalin may be used to target localized neuropathic pain 7.
- Combination Therapy: Combination therapy, involving the use of multiple agents with different mechanisms of action, may be necessary to manage both nociceptive and neuropathic pain components in patients with chronic LBP 7.