Etiology and Pharmacology of Neuropathic Pain

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 theα2δ-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

The Anti-Allodynic Gabapentinoids: Myths, Paradoxes, and Acute Effects

The gabapentinoids (pregabalin and gabapentin) are first line treatments for neuropathic pain. They exert their actions by binding to the α2δ accessory subunits of voltage-gated Ca2+ channels. Because these subunits interact with critical aspects of the neurotransmitter release process, gabapentinoid binding prevents transmission in nociceptive pathways. Gabapentinoids also reduce plasma membrane expression of voltage-gated Ca2+ channels but this may have little direct bearing on their therapeutic actions. In animal models of neuropathic pain, gabapentinoids exert an anti-allodynic action within 30 minutes but most of their in vitro effects are 30-fold slower, taking at least 17 hours to develop. This difference may relate to increased levels of α2δ expression in the injured nervous system. Thus, in situations where α2δ is experimentally upregulated in vitro, gabapentinoids act within minutes to interrupt trafficking of α2δ subunits to the plasma membrane within nerve terminals. When α2δ is not up-regulated, gabapentinoids act slowly to interrupt trafficking of α2δ protein from cell bodies to nerve terminals. This improved understanding of the mechanism of gabapentinoid action is related to their slowly developing actions in neuropathic pain patients, to the concept that different processes underlie the onset and maintenance of neuropathic pain and to the use of gabapentinoids in management of postsurgical pain

Acute anti-allodynic action of gabapentin in dorsal horn and primary somatosensory cortex: Correlation of behavioural and physiological data

Neuropathic pain is a debilitating consequence of neuronal injury or disease. Although first line treatments include the alpha-2-delta (a2d)-ligands, pregabalin and gabapentin (GBP), the mechanism of their anti-allodynic action is poorly understood. One specific paradox is that GBP relieves signs of neuropathic pain in animal models within 30min of an intraperitoneal (IP) injection yet its actions in vitro on spinal dorsal horn or primary afferent neurons take hours to develop. We found, using confocal Ca2þ imaging, that substantia gelatinosa neurons obtained ex vivo from rats subjected to sciatic chronic constriction injury (CCI) were more excitable than controls. We confirmed that GBP (100 mg/kg) attenuated mechanical allodynia in animals subject to CCI within 30min of IP injection.Substantia gelatinosa neurons obtained ex vivo from these animals no longer displayed CCI-induced increased excitability. Electrophysiological analysis of substantia gelatinosa neurons ex vivo suggest that rapidly developing in vivo anti-allodynic effects of GBP i) are mediated intracellularly, ii) involve actions on the neurotransmitter release machinery and iii) depend on decreased excitatory synaptic drive to excitatory neurons without major actions on inhibitory neurons or on intrinsic neuronal excitability. Experiments using in vivo Ca2þ imaging showed that 100 mg/kg GBP also suppressed the response of the S1 somatosensory cortex of CCI rats, but not that of control rats, to vibrotactile stimulation. Since the level of a2d1 protein is increased in primary afferent fibres after sciatic CCI, we suggest this dictates the rate of GBP action; rapidly developing actions can only be seen when a2d1 levels are elevated

Sensory neuron–derived NaV1.7 contributes to dorsal horn neuron excitability

Expression of the voltage-gated sodium channel NaV1.7 in sensory neurons is required for pain sensation. We examined the role of NaV1.7 in the dorsal horn of the spinal cord using an epitope-tagged NaV1.7 knock-in mouse. Immuno–electron microscopy showed the presence of NaV1.7 in dendrites of superficial dorsal horn neurons, despite the absence of mRNA. Rhizotomy of L5 afferent nerves lowered the levels of NaV1.7 in the dorsal horn. Peripheral nervous system–specific NaV1.7 null mutant mice showed central deficits, with lamina II dorsal horn tonic firing neurons more than halved and single spiking neurons more than doubled. NaV1.7 blocker PF05089771 diminished excitability in dorsal horn neurons but had no effect on NaV1.7 null mutant mice. These data demonstrate an unsuspected functional role of primary afferent neuron-generated NaV1.7 in dorsal horn neurons and an expression pattern that would not be predicted by transcriptomic analysis

A central mechanism of analgesia in mice and humans lacking the sodium channel NaV1.7

Deletion of SCN9A encoding the voltage-gated sodium channel NaV1.7 in humans leads to profound pain insensitivity and anosmia. Conditional deletion of NaV1.7 in sensory neurons of mice also abolishes pain, suggesting that the locus of analgesia is the nociceptor. Here we demonstrate, using in vivo calcium imaging and extracellular recording, that NaV1.7 knockout mice have essentially normal nociceptor activity. However, synaptic transmission from nociceptor central terminals in the spinal cord is greatly reduced by an opioid-dependent mechanism. Analgesia is also reversed substantially by central but not peripheral application of opioid antagonists. In contrast, the lack of neurotransmitter release from olfactory sensory neurons is opioid independent. Male and female humans with NaV1.7-null mutations show naloxone-reversible analgesia. Thus, inhibition of neurotransmitter release is the principal mechanism of anosmia and analgesia in mouse and human Nav1.7-null mutants

Comparison of ex vivo and in vitro actions of gabapentin in superficial dorsal horn and the role of extra-spinal sites of drug action

Although gabapentin (GBP) is a first-line treatment in the management of neuropathic pain, its mechanism of action is incompletely understood. We have previously shown, in rats made neuropathic following sciatic chronic constriction injury, that IP injection of 100 mg/kg GBP decreases overall excitability of spinal cord slices obtained ex vivo. Excitability was assessed using confocal imaging to monitor the amplitude of K+- induced increases in cytoplasmic Ca2+. This decrease in excitability involved a reduction in the frequency and amplitude of spontaneous EPSC’s (sEPSC) in putative excitatory substantia gelatinosa neurons and an increase in sEPSC frequency in putative inhibitory neurons. We used have whole-cell recording to compare these ex vivo actions of GBP with its acute in vitro effects on spinal cord slices obtained from neuropathic but drug-free rats. While GBP (100μM) decreased sEPSC amplitude and frequency in excitatory neurons in vitro in a similar fashion to effects observed ex vivo, sEPSC frequency in inhibitory neurons was decreased in vitro rather than increased. Acute in vitro application of GBP also failed to decrease the overall excitability of slices from neuropathic animals as monitored by confocal Ca2+ imaging. Since spinal cord slices in vitro are disconnected from the periphery and higher brain centres, the GBP-induced increase in sEPSC frequency in inhibitory neurons previously reported and seen ex vivo must result from extra-spinal actions. It may be attributable to alterations in descending neurotrophic control of dorsal horn circuitry