Acute herpetic pain in the elderly and with trigeminal involvement is believed to become longer and be liable to progress into post-herpetic neuralgia. However, acute herpetic pain in the elderly even with trigeminal involvement disappears rapidly, when skin lesions of herpes zoster are mild. Analysis of 1, 431 patients for whom the treatment of acute herpetic pain was begun within 14 days after the onset revealed that the severity of skin lesions of herpes zoster at the worst phase rather than age and involved region most influenced the duration of acute herpetic pain. Elderly patients and those with trigeminal involvement showed significantly higher frequencies of severe skin lesions of herpes zoster. These findings indicate that acute herpetic pain in the elderly and involving trigeminal region becomes longer because of higher frequencies of severe herpes zoster in the elderly and trigeminal involvement and not because of “aging” or “trigeminal involvement” itself. Results of treatment of acute herpetic pain should be analyzed with respect to severity of skin lesions of herpes zoster.
Herpes zoster is caused by reactivation of varicella zoster virus (VZV) within the sensory ganglia and spread through the peripheral nerves into the skin of the corresponding dermatomes. We studied the histological changes of the skin lesions in patients with herpes zoster and examined the distributions of VZV antigens using two monoclonal antibodies detecting either nucleocapsid or glycoproteins of VZV on paraffin sections of formalin fixed biopsy material. VZV infection within the skin begins at the follicular epithelia or lower epidermis at first, then spreads to the macrophages, fibroblasts, vascular endothelia of the small vessels, and perineurium of cutaneous nerves in the dermis. Viral infections of the vascular endothelia around the involved follicles or vesiculated epidermis induce severe inflammation such as leukocytoclastic vasculitis and tissue destruction. In regard to the cutaneous nerves, VZV infections are observed within the perinerium, Schwann cells and vascular endothelia of neighboring vessels in the early erythematous or vesicular stages. In the full developed pustular or ulcerated stages, inflammatory cell infiltrates within the nerves and degeneration of the myelin sheath were observed. In the stage of postherpetic neuralgia, increase of thin nerve fibers without myelin sheath and intra fascicular fibrosis were observed.
Postherpetic neuralgia (PHN) is neuropathic pain syndrome. PHN occurred after herpes zoster which causes the peripheral nerve inflammation. PHN has been known to be relatively refractory to the standard analgesic agents, such as non-steroidal anti-inflammatory drugs and opioids. Anti-depressant drugs, anti-arrhythmic drugs and anti-convulsants are usually used for the treatment of PHN, but the results of this treatment are not always satisfactory. N-methyl-D-aspartate (NMDA) receptor dependent spinal sensitization has been shown to play an important role in the maintenance of neuropathic pain and NMDA receptor antagonists have been reported to alleviate the level of neuropathic pain in the animal model. Ketamine and dextromethorphan are the clinically available NMDA receptor antagonists and I tried to treat PHN with epidural ketamine and oral dextromethorphan. Both epidural ketamine and oral dextromethorphan successfully treated PHN. This suggested that PHN is maintained by the NMDA receptor dependent spinal sensitization. Recently, three new pharmacological approaches, such as systemic gabapentin administration, intrathecal admnistration of N-type voltage dependent Ca2+channel (VDCC) blocker and intrathecal nociceptin injection, have been tested for the treatment of neuropathic pain in the animal models. Gabapentin is a newly developed anti-convulsant drug. Oral gabapentin has already reported to treat PHN in the clinical situation. Release of neurotransmitter is regulated by the influx of Ca2+ into the nerve terminals through VDCCs, such as N-type VDCC. N-type VDCC blockers inhibit the substance P and glutamate release and intrathecal injection of N-type VDCC attenuates the level of neuropathic pain in the animal model. Nociceptin is an endogenous agonist for the opioid receptor likel receptor. Nociceptin has been reported to depress the spinal sensitization and to alleviate the level of neuropathic pain in the animal model. I believe that these three drugs will be the major approach to the treatment of PHN in near future.
Prostaglandins (PGs) are ubiquitously distributed in virtually all mammalian tissues and organs, and it has been well documented that PGs are involved in various aspects of inflammation including pain. Accumulating evidence indicates that PGs are critical for the processing of pain, not only in the periphery but also at the spinal level. We showed that intrathecal (i.t.) administration of PGD2 and PGE2 induced hyperalgesia to noxious stimuli and that i.t. PGE2 and PGF2α induced allodynia, a state of discomfort and pain evoked by innocuous stimuli, in conscious mice. PGF2α augmented the allodynia evoked by PGE2 additively at submaximal doses. On the other hand, PGD2 blocked the allodynia induced by PGE2, but did not affect the PGF2α-induced one, suggesting that the mechanisms of allodynia induced by PGE2 and PGF2α may be different. Both glutamate and nitric oxide (NO) have recently been paid much attention because they are reported to be involved in long-term potentiation (LTP), a potential cellular mechanism for memory and learning. We demonstrated from pharmacological studies that PGE2-and PGF2α-induced allodynia are mediated by activation of glutamate receptors and following NO production, but in a defferent manner. We have recently secceeded in purification and characterization of a novel heptadecapeptide called nociceptin in bovine brains as an endogenous ligand for ROR-C, an opioid receptor homologue cloned from rat cerebrum. Intrathecal administration of nociceptin induced allodynia by innocuous tactile stimuli and hyperalgesia by noxious thermal stimuli in conscious mice. PGD2 blocked the allodynia induced by nociceptin, but did not affect the nociceptin-induced hyperal-gesia. Furthermore, the allodynia caused by nociceptin was dose-dependently blocked by glycine. These results demonstrate that there exist at least two mechanisms for induction of allodynia: disinhibition through anti-glycinergic effect and hyperexcitability through a pathway that includes the glutamate receptor-NO-cGMP system in the mouse spinal cord. These results also imply that endogenous PGD2 may play a modulatory role in the appearance of allodynia under physiological conditions. In a series of experiments, we demonstrated that PGs play central roles in pain transmission with interactions of other neurotransmitter systems, especially with the opioid system.
Neuropathic pain is defined as the pain that results from functional abnormalities of the nervous system: for example, deafferentiation or dysesthesia, referring to an unfamiliar unpleasant sensation, persisting for a long duration even in the absence of ongoing active tissue-damaging process to explain it. Although peripheral neural mechanisms are likely to contribute, in part, to the neuropathic pain, the persistence of pain after healing of the damaged tissue suggests that plastic changes in the CNS, including the spinal cord, may also play an important role in processing the transmission of neuropathic pain. Present study was designed to investigate the plastic change in synaptic transmission at the spinal level using whole cell patch clamp recordings from substantia gelatinosa (SG, lamina II of Rexed) neurons in spinal cord slices which retained an attached dorsal root dissected from adult rats with or without sciatic nerve transection (SNT). The normal and SNT rats showed no significant differences in passive and active membrane characteristics, including membrane potential, input resistance and configuration of action potential and spike after potentials. In the control rats, primary afferent stimuli with intensity sufficient to activate Aδ afferents elicited a monosynaptic fast excitatory postsynaptic current (EPSC) in 50% of neurons and a polysynaptic EPSC in 30%. In only 5% of neurons, the polysynaptic EPSC was elicited with intensity sufficient to activate Aβ afferents. In the SNT rats, however, a polysynaptic EPSC with a long latency was evoked in 79% of neurons by activation of Aβ afferents. Increasing stimulus intensity sufficient to activate Aδ afferents produced a EPSC which had a short and constant latency, suggesting that the Aδ afferents were functionally preserved after peripheral nerve transection. Aβ afferent-evoked monosynaptic EPSC was observed in only 2 of 34 neurons. The conduction velocity and minimum stimulus intensity for activation of Aβ and Aδ afferent fibers, assessed by intracellular recordings from dorsal root ganglion neurons, were not significantly altered in normal and sciatic nerve transected rats. These observations suggest that synaptic plasticity may occur in a subset of dorsal horn neurons and/or terminal arborization of primary afferent, particularly Aβ afferents, following nerve transection, consequently sensory information conveyed by Aβ afferents is transmitted to SG neurons which receive a few Aβ afferent inputs in the normal condition. This plastic changes in synaptic organization in the spinal dorsal horn may, therefore, underlie in part pathological pain such as allodynia and dysesthesia.
After chicken pox, varicella-zoster virus (VZV) establishes latent infection in satellite cells in sensory ganglia and eventually reactivates as acute herpes zoster (AHZ) or shingles. The reactivation leads to infection of other cells within the ganglion and results in inflammation of the posterior spinal cord, peripheral nerve and skin. Pain in AHZ is primarily due to inflammation of the infected structures. Epidural block soothes inflammation in the epineurium and controls the ongoing afferent barrage in the affected nerve fibers, preventing sensitization of second order neurons. Postherpetic neuralgia (PHN) is the commonest and perhaps most-dreaded complication of AHZ. Pain of PHN is often of three types; ongoing pain, superimposed paroxysmal pain and allodynia. An ongoing pain is described as burning, aching or tearing, and a superimposed paroxysmal pain as stabbing or electric shock-like. For many patients, sensations evoked by clothes contact or skin stretching with movement constitute the most unbearable part of PHN. There are sensory deficits affecting all modalities in the involved dermatomes, indicative of partial deafferentation. Intravenous lidocaine produces significant relief for PHN, and pain relief with topically applied lidocaine has also been reported. It is likely that ectopic impulses are generated from surviving axons and induce hypersensitivity of second-order neurons. The ectopic impulses are abolished by concentrations of lidocaine much lower than that required for blocking normal axonal conduction. Unfortunately lidocaine is not always effective. Thus deafferentation hyperactivity of second order neurons is another possible explanation. Allodynia is most often elicited by innocuous moving stimuli, and the mechanical allodynia appears to be mediated by large fibers. This implies abnormal synaptic connectivity at the spinal-cord level between large afferent fibers and the central pain signaling secondary neurons. It has been hypothesized that deafferentation of nociceptive fibers leads to vacancies at the level of second-order neurons, enabling these neurons to create new working synaptic connections with surviving large fibers. This reorganization may involve WDR neurons. Then the wind up response of WDR neurons which normally occurs in response to repetitive C fiber stimulation through activation of NMDA receptors, may be brought about by large fiber inputs. This may account for the wind up of tactile allodynia in PHN.