Injury to or disease of the nervous system can invoke chronic and sometimes intractable neuropathic pain. Many parallel, interdependent, and time-dependent processes, including neuroimmune interactions at the peripheral, supraspinal, and spinal levels, contribute to the etiology of this “disease of pain.” Recent work emphasizes the roles of colony-stimulating factor 1, ATP, and brain-derived neurotrophic factor. Excitatory processes are enhanced, and inhibitory processes are attenuated in the spinal dorsal horn and throughout the somatosensory system. This leads to central sensitization and aberrant processing such that tactile and innocuous thermal information is perceived as pain (allodynia). Processes involved in the onset of neuropathic pain differ from those involved in its long-term maintenance. Opioids display limited effectiveness, and less than 35% of patients derive meaningful benefit from other therapeutic approaches. We thus review promising therapeutic targets that have emerged over the last 20 years, including Na⁺, K⁺, Ca²⁺, hyperpolarization-activated cyclic nucleotide–gated channels, transient receptor potential channel type V1 channels, and adenosine A3 receptors. Despite this progress, the gabapentinoids retain their status as first-line treatments, yet their mechanism of action is poorly understood. We outline recent progress in understanding the etiology of neuropathic pain and show how this has provided insights into the cellular actions of pregabalin and gabapentin. Interactions of gabapentinoids with the α2δ-1 subunit of voltage-gated Ca²⁺ channels produce multiple and neuron type-specific actions in spinal cord and higher centers. We suggest that drugs that affect multiple processes, rather than a single specific target, show the greatest promise for future therapeutic development.

Intractable neuropathic pain is a frequent consequence of nerve injury or disease. When peripheral nerves are injured, damaged axons undergo Wallerian degeneration. Schwann cells, mast cells, fibroblasts, keratinocytes and epithelial cells are activated leading to the generation of an “inflammatory soup” containing cytokines, chemokines and growth factors. These primary mediators sensitize sensory nerve endings, attract macrophages, neutrophils and lymphocytes, alter gene expression, promote post-translational modification of proteins, and alter ion channel function in primary afferent neurons. This leads to increased excitability and spontaneous activity and the generation of secondary mediators including colony stimulating factor 1 (CSF-1), chemokine C-C motif ligand 21 (CCL-21), Wnt3a, and Wnt5a. Release of these mediators from primary afferent neurons alters the properties of spinal microglial cells causing them to release tertiary mediators, in many situations via ATP-dependent mechanisms. Tertiary mediators such as BDNF, tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β), and other Wnt ligands facilitate the generation and transmission of nociceptive information by increasing excitatory glutamatergic transmission and attenuating inhibitory GABA and glycinergic transmission in the spinal dorsal horn. This review focusses on activation of microglia by secondary mediators, release of tertiary mediators from microglia and a description of their actions in the spinal dorsal horn. Attention is drawn to the substantial differences in the precise roles of various mediators in males compared to females. At least 25 different mediators have been identified but the similarity of their actions at sensory nerve endings, in the dorsal root ganglia and in the spinal cord means there is considerable redundancy in the available mechanisms. Despite this, behavioral studies show that interruption of the actions of any single mediator can relieve signs of pain in experimental animals. We draw attention this paradox. It is difficult to explain how inactivation of one mediator can relieve pain when so many parallel pathways are available.

Sensory abnormalities generated by nerve injury, peripheral neuropathy or disease are often expressed as neuropathic pain. This type of pain is frequently resistant to therapeutic intervention and may be intractable. Numerous studies have revealed the importance of enduring increases in primary afferent excitability and persistent spontaneous activity in the onset and maintenance of peripherally induced neuropathic pain. Some of this activity results from modulation, increased activity and /or expression of voltage-gated Na⁺ channels and hyperpolarization-activated cyclic nucleotide–gated (HCN) channels. K⁺ channels expressed in dorsal root ganglia (DRG) include delayed rectifiers (K_v1.1, 1.2), A-channels (K_v1.4, 3.3, 3.4, 4.1, 4.2, and 4.3), KCNQ or M-channels (K_v7.2, 7.3, 7.4, and 7.5), ATP-sensitive channels (K_IR6.2), Ca²⁺-activated K⁺ channels (K_Ca1.1, 2.1, 2.2, 2.3, and 3.1), Na⁺-activated K⁺ channels (K_Ca4.1 and 4.2) and two pore domain leak channels (K_2p; TWIK related channels). Function of all K⁺ channel types is reduced via a multiplicity of processes leading to altered expression and/or post-translational modification. This also increases excitability of DRG cell bodies and nociceptive free nerve endings, alters axonal conduction and increases neurotransmitter release from primary afferent terminals in the spinal dorsal horn. Correlation of these cellular changes with behavioral studies provides almost indisputable evidence for K⁺ channel dysfunction in the onset and maintenance of neuropathic pain. This idea is underlined by the observation that selective impairment of just one subtype of DRG K⁺ channel can produce signs of pain in vivo. Whilst it is established that various mediators, including cytokines and growth factors bring about injury-induced changes in DRG function and excitability, evidence presently available points to a seminal role for interleukin 1β (IL-1β) in control of K⁺ channel function. Despite the current state of knowledge, attempts to target K⁺ channels for therapeutic pain management have met with limited success. This situation may change with the advent of personalized medicine. Identification of specific sensory abnormalities and genetic profiling of individual patients may predict therapeutic benefit of K⁺ channel activators.

Neuropathic pain can result from injury to, or disease of the nervous system. It is notoriously difficult to treat. Peripheral nerve injury promotes Schwann cell activation and invasion of immunocompetent cells into the site of injury, spinal cord and higher sensory structures such as thalamus and cingulate and sensory cortices. Various cytokines, chemokines, growth factors, monoamines and neuropeptides effect two-way signalling between neurons, glia and immune cells. This promotes sustained hyperexcitability and spontaneous activity in primary afferents that is crucial for onset and persistence of pain as well as misprocessing of sensory information in the spinal cord and supraspinal structures. Much of the current understanding of pain aetiology and identification of drug targets derives from studies of the consequences of peripheral nerve injury in rodent models. Although a vast amount of information has been forthcoming, the translation of this information into the clinical arena has been minimal. Few, if any, major therapeutic approaches have appeared since the mid 1990's. This may reflect failure to recognise differences in pain processing in males vs. females, differences in cellular responses to different types of injury and differences in pain processing in humans vs. animals. Basic science and clinical approaches which seek to bridge this knowledge gap include better assessment of pain in animal models, use of pain models which better emulate human disease, and stratification of human pain phenotypes according to quantitative assessment of signs and symptoms of disease. This can lead to more personalized and effective treatments for individual patients. Significance statement: There is an urgent need to find new treatments for neuropathic pain. Although classical animal models have revealed essential features of pain aetiology such as peripheral and central sensitization and some of the molecular and cellular mechanisms involved, they do not adequately model the multiplicity of disease states or injuries that may bring forth neuropathic pain in the clinic. This review seeks to integrate information from the multiplicity of disciplines that seek to understand neuropathic pain; including immunology, cell biology, electrophysiology and biophysics, anatomy, cell biology, neurology, molecular biology, pharmacology and behavioral science. Beyond this, it underlines ongoing refinements in basic science and clinical practice that will engender improved approaches to pain management.