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Mechanical dynamic allodynia is a hallmark symptom of postherpetic neuralgia, but the mechanisms are unclear. This study examined the participation of injury to sensory C-fiber and A-fiber neurons in postherpetic dynamic allodynia. Percutaneous inoculation of mice with herpes simplex virus type-1 caused zoster-like skin lesions and dynamic allodynia, which persisted after lesion healed. In postherpetic mice, the intensity of dynamic allodynia was positively and negatively correlated with the withdrawal latency of nociceptive response to heat and the intensity of aversive response to capsaicin, respectively. Calcitonin gene-related peptide immunoreactivity (a C-fiber marker) was markedly reduced, but neurofilament 200 immunoreactivity (an A-fiber neuron marker) was unchanged in the scarred skin of postherpetic mice. In the affected dorsal root ganglion of postherpetic mice, peripherin-immunoreactive (a C-fiber neuron marker) neurons reduced significantly, whereas neurofilament 200-immunoreactive neurons did not. These results suggest that postherpetic dynamic allodynia is associated with injury to sensory C-fiber neurons and little damage to A-fiber neurons.

Percutaneous inoculation of mice with herpes simplex virus type-1 produces marked dynamic allodynia in the zosteriform dermatome. In this study, we examined the electrophysiological excitability of the wide-dynamic range neuron in the spinal dorsal horn and the tibial nerve in response to mechanical (brush, punctum, and pinch) stimuli in mice with herpetic allodynia. The excitatory response of wide-dynamic range neurons to brush, but neither punctum nor pinch, stimulation of the zosteriform dermatome was increased in herpetic mice. The responses of the tibial nerve to all kinds of mechanical stimuli examined were decreased. These results suggest that dynamic allodynia in the affected dermatome is because of the increased excitability of wide-dynamic range neurons, but not primary afferents, to brush stimulation.

This study was conducted to identify the mechanosensitive dorsal horn neurons involved in allergic itch. We examined 98 units responsive to cutaneous allergy; 90 showed only immediate responses, which subsided before the onset of itch-related behavior and eight showed immediate and sustained responses, the latter of which was similar in duration to itch-related behavior, suggesting the involvement of sustained units in itch signaling. Sustained units were localized in the superficial, but not deep, layers of the dorsal horn. They were wide dynamic range or nociceptive specific, but not low threshold and four of eight were noxious heat sensitive. The results suggest that a small minority of neurons in the superficial dorsal horn are involved in allergic itch signals.

Peripheral action of mu-opioid receptor agonist inhibits mechanical allodynia in mice with herpetic pain. Mechanical allodynia is mainly mediated by Abeta fibers, whereas mu-opioid receptors are present in C and Adelta fibers. This study was conducted to address this discrepancy. Neonatal capsaicin treatment, which almost abolished aversive response to capsaicin, did not affect herpetic allodynia and antiallodynic effect of local injection of morphine. Although mu-opioid receptor was chiefly expressed in small-sized and medium-sized sensory neurons in naive mice, it was induced in large sensory neurons in mice with herpetic pain. Viral propagation in the sensory ganglion may induce mu-opioid receptor expression in Abeta fibers, which may be responsible for the inhibitory action of local opioids on mechanical allodynia in mice with herpetic pain.

We examined whether different itch signals converge on the same dorsal horn neurons in mice. Intradermal injections of histamine and SLIGRL-NH2 (protease-activated receptor-2 agonist) induced scratching in naive mice and so did mosquito allergen in sensitized mice. These stimuli induced Fos expression in cells in the superficial dorsal horn. Fos-positive cells were mainly distributed within the isolectin B4-labeled region (inner aspect of lamina II) after histamine injection. In contrast, they were in the region dorsal to the isolectin B4-labeled region after injections of SLIGRL-NH2 and mosquito allergen. These results suggest that allergic itch signal is mediated by primary afferents expressing protease-activated receptor-2 and the neurons receiving signals of protease-associated itch and allergy-associated itch are different from those of histamine-induced itch.

Glutamate is considered an important pain transmitter and responsible for inflammatory hyperalgesia, but quantitative and topographical changes in glutamate release in the dorsal horn during peripheral inflammation have not been characterized. To address this issue, image analysis with a confocal laser scanning microscope was performed for quantitatively mapping capsaicin-evoked glutamate release from the lumbar cord slice of rats following unilateral adjuvant inoculation to the hind-paw. Capsaicin induced glutamate release from laminae I, II and X in the spinal cord of the adjuvant-treated and untreated sides, without apparent release from laminae III-V. The concentration of released glutamate in laminae I, II and X was higher on the adjuvant-treated side than on the untreated side. The results suggest that adjuvant inflammation increases glutamate release from capsaicin-sensitive primary afferents in laminae I, II and X.

Nociceptin has been suggested to be involved in nociceptive processing in the spinal dorsal horn. To investigate whether the biosynthesis of nociceptin is altered in animals with nociceptive hypersensitivity, we examined effects of peripheral inflammation on the expression of prepronociceptin mRNA, especially in the dorsal root ganglion of the rat. Although little or no expression of prepronociceptin mRNA was observed in the dorsal root ganglia of naive animals, carrageenan-elicited inflammation markedly induced its expression, peaking within 30 min, a time when nociceptive hypersensitivity was not yet apparent. The results suggest that peripheral inflammation induced nociceptin expression in primary sensory neurons, which may be associated with the production of nociceptive hypersensitivity.

Although spinal neurons expressing BB2 bombesin receptors are suggested to be involved in itch transmission, their role in pathological itch remains unknown. Because itch is often observed in patients with herpes zoster, we examined the role of BB2 receptor-expressing spinal neurons in herpes-associated itch in mice. Transdermal inoculation of human herpes virus 1 on the midflank produced herpes zoster-like skin lesions and caused the mice to scratch (itch-related behavior) and lick (pain-related behavior) the affected skin. Ablation of BB2 receptor-expressing spinal neurons by intrathecal treatment with a bombesin-saporin conjugate decreased the scratching but not the licking. Intrathecal administration of the BB2 receptor antagonist Leu13-ψ-(CH2NH)Leu14-bombesin decreased BB2 receptor agonist GRP(18-27)-induced scratching in naive mice but not herpes-associated scratching. The present results suggest that BB2 receptor-expressing spinal neurons transmit herpes-associated itch by BB2 receptor-independent signaling.

We investigated whether IgE receptors are expressed on sensory neurons in mice. Immunostaining revealed that the high affinity IgE receptor FcepsilonRI was expressed in cultured dorsal root ganglion cells and that FcepsilonRI-immunoreactive cells were mainly positive for the pan-neuronal marker protein gene product 9.5. Many FcepsilonRI-immunoreactive neurons were small or medium in size. IgE was bound to cultured neurons but not glial cells from the ganglia. FcepsilonRI-immunoreactive cells were also positive for the high affinity IgG receptor FcgammaRI. The expression level of FcepsilonRI was lower than that of FcgammaRI. FcepsilonRI-like immunoreactivity was localized on nerve fibers in the skin. The results suggest that IgE acts directly on primary sensory neurons as well as mast cells.

Using nociceptin-receptor-deficient mice, we studied the participation of nociceptin in herpetic and postherpetic allodynia in mice. Although nociceptin-receptor deficiency did not affect the development of skin lesions and herpetic allodynia, it prevented postherpetic allodynia. Messenger ribonucleic acid (mRNA) of pronociceptin increased in the dorsal horn of lumbar enlargement on day 6, but not on day 40, after inoculation. No changes were observed in the mRNA of the nociceptin receptor. Inhibition of herpetic allodynia by repeated oral administration of gabapentin (100 mg/kg) alleviated the overexpression of mRNA of pronociceptin, as well as the severity of postherpetic allodynia. These results suggest that the spinal nociceptin system is involved in the transitional process from herpetic allodynia to postherpetic allodynia.