Glycine Inhibitory Dysfunction Induces a Selectively Dynamic, Morphine-Resistant, and Neurokinin 1 Receptor- Independent Mechanical Allodynia

Abstract

Dynamic mechanical allodynia is a widespread and intractable symptom of neuropathic pain for which there is a lack of effective therapy. We recently provided a novel perspective on the mechanisms of this symptom by showing that a simple switch in trigeminal glycine synaptic inhibition can turn touch into pain by unmasking innocuous input to superficial dorsal horn nociceptive specific neurons through a local excitatory, NMDA-dependent neural circuit involving neurons expressing the gamma isoform of protein kinase C. Here, we further investigated the clinical relevance and processing of glycine disinhibition. First, we showed that glycine disinhibition with strychnine selectively induced dynamic but not static mechanical allodynia. The induced allodynia was resistant to morphine. Second, morphine did not prevent the activation of the neural circuit underlying allodynia as shown by study of Fos expression and extracellularsignal regulated kinase phosphorylation in dorsal horn neurons. Third, in contrast to intradermal capsaicin injections, light, dynamic mechanical stimuli applied under disinhibition did not produce neurokinin 1 (NK1) receptor internalization in dorsal horn neurons. Finally, light, dynamic mechanical stimuli applied under disinhibition induced Fos expression only in neurons that did not express NK1 receptor. To summarize, the selectivity and morphine resistance of the glycine-disinhibition paradigm adequately reflect the clinical characteristics of dynamic mechanical allodynia. The present findings thus reveal the involvement of a selective dorsal horn circuit in dynamic mechanical allodynia, which operates through superficial lamina nociceptive-specific neurons that do not bear NK1 receptor and provide an explanation for the differences in the pharmacological sensitivity of neuropathic pain symptoms.

Sodium Channel Nav1.7 Is Essential for Lowering Heat Pain Threshold after Burn Injury

“…In one scenario, warm-sensitive neurons affected by hindpaw burn would become hyperexcitable due to changes in the electrophysiological properties of Na v 1.7 and would produce more action potentials in response to their adequate stimulus (e.g., 40°C). It is not entirely clear in this case how warm-sensitive afferents would gain the ability to communicate via heat-pain pathways in the spinal cord, although a system analogous to the disinhibition demonstrated in touch-pain for the mechanical modality (Yaksh, 1989;Sivilotti and Woolf, 1994;Torsney and MacDermott, 2006;Miraucourt et al, 2009) could be involved. This would require warm-sensitive neurons to be prewired to second-order pain-sensitive neurons, and additionally invokes changes in spinal interneurons.…”

Long-term potentiation of glycinergic synapses triggered by interleukin 1β

“…Inhibitory interneurons of the spinal dorsal horn have been proposed to gate the flow of innocuous and nociceptive sensory information from the periphery to higher brain centers (12), and supportive evidence for this idea is growing (13)(14)(15)(16)(17). Loss of GABAergic/glycinergic inhibition contributes to enhanced transmission of nociceptive signals through the dorsal horn circuit during pain states, resulting in hyperalgesia and allodynia (3,(18)(19)(20). For example, polysynaptic A-fiber inputs onto neurokinin 1 receptor (NK1R)-expressing projection neurons become apparent only when GABA A R and GlyRs are pharmacologically blocked, indicating that under conditions of disinhibition, nonnoxious mechanical stimuli can drive nociceptive-specific projection pathways and elicit allodynia (21).…”

Evaluation of a novel mouse model of intracisternal strychnine-induced trigeminal allodynia

“…The similarities of intracisternal strychnine-induced glycine disinhibition to clinical trigeminal neuropathy include the presence of dynamic allodynia 1 and its restriction to the distribution of the trigeminal nerve distribution. 4 Strychnine did not produce changes in sensorimotor activity in areas other than the trigeminal distribution, allowing for assessment of nervous system dysfunction specific to the trigeminal nerve.…”

“…Recently, trigeminal glycinergic inhibitory dysfunction has been shown in rats to produce localized dynamic allodynia, a central feature of human trigeminal neuralgia. 4,5 While electrophysiological, behavioural, and pharmacological studies in vivo have shown that this produces many of the features of clinical trigeminal neuropathies, the model requires validation for clinically effective agents. 6 Nonetheless, the clinically ineffective agent, morphine, has also been shown to be ineffective in reversing rat dynamic mechanical allodynia resulting from strychnine-induced allodynia.…”

“…This suggests a possible relationship with the human disorder. 4,5 In this study, we developed and evaluated an alternative mouse preparation of intracisternal (i.c.) strychnine-based trigeminal neuropathic pain and examined the effects of artificial cerebrospinal fluid (aCSF), morphine, and carbamazepine in order to assess predictive efficacy for screening trigeminal neuralgia drug candidates.…”