Diseases and injuries to the nervous system can lead to a devastating chronic pain condition called neuropathic pain. We review changes that occur in the peripheral nervous system that may play a role in this disease. Common animal models for neuropathic pain involve an injury to one or more peripheral nerves. Following such an injury, the nerve fibers that have been injured exhibit many abnormal properties including the development of spontaneous neural activity as well as a change in the expression of certain genes in their cell body. Recent data indicate that adjacent, uninjured nerve fibers also exhibit significant changes. These changes are thought to be driven by injury-induced alterations in the milieu surrounding the uninjured nerve and nerve terminals. Thus, alteration in neural signaling in both injured and uninjured neurons play a role in the development of neuropathic pain after peripheral nerve injury.
Animals ; Disease Models, Animal ; Nerve Fibers ; pathology ; Neuralgia ; physiopathology ; Neurons, Afferent ; cytology ; Peripheral Nerve Injuries ; physiopathology

PURPOSE: Pain from osteoarthritis (OA) is generally classified as nociceptive (inflammatory). Animal models of knee OA have shown that sensory nerve fibers innervating the knee are significantly damaged with destruction of subchondral bone junction, and induce neuropathic pain (NP). Our objective was to examine NP in the knees of OA patients using painDETECT (an NP questionnaire) and to evaluate the relationship between NP, pain intensity, and stage of OA. MATERIALS AND METHODS: Ninety-two knee OA patients were evaluated in this study. Pain scores using Visual Analogue Scales (VAS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), painDETECT, duration of symptoms, severity of OA using the Kellgren-Lawrence (KL) system, and amount of joint fluid were evaluated and compared using a Spearman's correlation coefficient by rank test. RESULTS: Our study identified at least 5.4% of our knee OA patients as likely to have NP and 15.2% as possibly having NP. The painDETECT score was significantly correlated with the VAS and WOMAC pain severity. Compared with the painDETECT score, there was a tendency for positive correlation with the KL grade, and tendency for negative correlation with the existence and amount of joint fluid, but these correlations were not significant. CONCLUSION: PainDETECT scores classified 5.4% of pain from knee OA as NP. NP tended to be seen in patients with less joint fluid and increased KL grade, both of which corresponded to late stages of OA. It is important to consider the existence of NP in the treatment of knee OA pain.
Aged ; Aged, 80 and over ; Female ; Humans ; Knee/pathology/physiopathology ; Male ; Middle Aged ; Neuralgia/*physiopathology ; Osteoarthritis, Knee/*physiopathology

Adult ; Aged ; Cauda Equina ; pathology ; physiopathology ; Female ; Humans ; Hypesthesia ; pathology ; Male ; Middle Aged ; Neuralgia ; pathology ; physiopathology ; Spinal Cord Injuries ; pathology ; physiopathology

Dorsal root ganglion (DRG) neurons have peripheral terminals in skin, muscle, and other peripheral tissues, and central terminals in the spinal cord dorsal horn. Hyperpolarization-activated current (I(h)) of the hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels are present in the DRG. The genes encoding HCN channels have four subtypes named HCN1 to HCN4. HCN channels are permeable to both K(+) and Na(+). They underlie the depolarization that modulates the rhythmic generations of action potentials (APs), contribute to the resting membrane potential, and modify the waveform of propagated synaptic and generator potentials. Neuropathic pain is characterized by spontaneous pain, hyperalgesia and allodynia. After spinal nerve injury, the cell bodies of the primary sensory neurons in segmental DRG become hyperexcitable, characterized for some neurons by the presence of spontaneous firing (or ectopic discharge). In the following, we summarize our observations on the role of HCN channels in DRG neurons in neuropathic pain. 1 HCN subtypes and I(h) in DRG neurons Immunohistochemical staining revealed a subgroup of neurons in the DRG that were stained with rabbit polyclonal antibodies specific for HCN1, 2, 3 and 4. The most prominently expressed HCN subtype was HCN1. HCN1-positive cells in DRG were medium to large in size and doubly labeled with neurofilament-200 (NF-200), and were not labeled with isolectin B4 (IB4), a C fiber marker. In contrast, HCN2, 3 or 4 was expressed in all DRG neurons at a lower level. HCN4 was confined to small neurons. DRG neurons expressed I(h). When membrane was hyperpolarized, the channel was activated, mediating a slowly activated, inward current. I(h) was distributed mainly in large and medium-sized DRG neurons. 2 Changes in expression of HCN in DRG after spinal nerve ligation Western blotting was used to detect the changes in the expression of HCN subtypes in the DRG after spinal nerve ligation. HCN1 mRNA and protein were reduced in the DRG whose spinal nerve had been ligated. HCN1 expression was decreased to the lowest level at day 14 and restored at day 28 after spinal nerve ligation. HCN2 mRNA and medium molecular weight protein was also decreased in spinal-nerve ligated DRG. HCN3 and 4 in the same ganglion remained unchanged as evidenced by immunohistochemical staining, until day 28 when they became significantly decreased. HCN4 mRNA in DRG did not change, and protein expression slightly increased. Interestingly, abundant axonal accumulation of HCN channel protein at the injured sites in chronic constriction injury (CCI) rats. Electron immunomicroscopy showed strong positive immunolabeling on the axolemma of myelinated thick axons. 3 Role of I(h) in neuronal excitability and ectopic discharges after spinal nerve ligation ZD7288, a specific I(h) blocker, inhibited I(h) in a time- and concentration-dependent manner. With patch-clamp recording on acutely isolated DRG neurons, it was found that ZD7288 perfusion resulted in a decrease of both I(h) activity and the activation time constant. ZD7288 decreased the number of repetitive APs and caused an increase in AP rise time, accompanied by a small hyperpolarization of the membrane resting potential. The results demonstrated that I(h) was involved in AP firing, and possessed the physiological functions to facilitate neuronal excitability and ectopic firing. Extracellular electrophysiological recording from dorsal root fibers associated with the spinal nerve-ligated ganglion revealed three different firing patterns of ectopic discharges: tonic or regular, bursting and irregular. The average frequency of ectopic discharges and the proportions of active filaments also changed rapidly, both parameters reaching a peak within 24 h then declining gradually in the following days. It was also found that proportions of three different firing patterns changed dynamically over time. The tonic and bursting types were dominant patterns in the first 24 h, while the irregular became the only pattern at day 14. We found that all three firing patterns (tonic, bursting and irregular) were dose- and time-dependently inhibited by local application of ZD7288 to DRG. The rate of suppression was negatively related to the frequency of firing prior to the application of ZD7288. We also found that, while the tonic firing pattern was gradually transformed to bursting type by application of 100 mumol/L ZD7288, it could be transformed to integer multiples firing by 1000 mumol/L ZD7288. 4 Effects of administration of ZD7288 on mechanical allodynia after spinal nerve ligation or CCI After spinal nerve ligation, i.t. injection of 30 mug ZD7288 significantly increased the 50% paw withdrawal threshold, ipsilateral to the ligated nerve. ZD7288 had no effect if the dose was lower than 15 mug, but resulted in motor deficits if the dose was higher than 60 mug. ZD7288 produced much better effects in the early stage (5 or 14 days after spinal nerve ligation) than that in the late stage (28 days after spinal nerve ligation). In CCI rats, ZD7288 application to the injured sited also significantly suppressed the ectopic discharges from injured nerve fibers with no effect on impulse conduction. Moreover, mechanical allodynia was inhibited. In conclusion, these results demonstrated that I(h) participated in the development and maintenance of peripheral sensitivity associated with neuropathic pain and that it is a potential target for the design of novel analgesics in the future.
Action Potentials ; Animals ; Cyclic Nucleotide-Gated Cation Channels ; metabolism ; Ganglia, Spinal ; physiopathology ; Hyperalgesia ; physiopathology ; Membrane Potentials ; Nerve Fibers ; pathology ; Neuralgia ; physiopathology ; Neurons, Afferent ; pathology ; Rats ; Rats, Sprague-Dawley ; Spinal Nerves ; pathology

Herpes zoster is a relapse of varicella. In certain cases, long-term pain and hyperhidrosis have been noted. Appearance of herpes zoster during pregnancy is infrequent. We described hyperhidrosis and pain treatment using glycopirrolate cream in a pregnant woman with herpetic neuralgia. A 32 year old woman, 21 weeks pregnant with second child, complained to her gynecologist of the appearance of a vesicular rash on the left half of the forehead that progressed toward her left eyelid, accompanied by lancinating pain, allodynia, hyperhidrosis and small edema, blepharitis and conjunctivitis. Following clinical and laboratory tests, she was diagnosed with herpes zoster ophtalmicus. Aciclovir therapy was administered 800 mg orally five times daily for seven days. Pain therapy was initiated with amitriptilline. We discontinued amitriptilline therapy after 10 days because of appearance of unwanted side effects. After skin changes ceased, we introduced Lidocaine patch into pain therapy which reduced the allodynia, but not the lancinating pain and hyperhidrosis. At that time we began using glycopirrolate cream which reduced pain intensity by 28.5% within 24 hours, and completely eliminated hyperhidrosis. After 48 hours of use, the pain completely disappeared. During the Glycopirrolate cream therapy, there were no side effects. This is a first report to document that a topical Glycopirrolate cream has a beneficial effect in a patient with hyperhidrosis and herpetic neuralgia.
Adjuvants, Anesthesia/administration & dosage/*therapeutic use ; Administration, Topical ; Adult ; Female ; Glycopyrrolate/administration & dosage/*therapeutic use ; Herpes Zoster/*drug therapy/pathology ; Humans ; Neuralgia/pathology/*physiopathology ; Pregnancy

OBJECTIVETo investigate the changes of GABA-activated currents in isolated dorsal root ganglion neurons in rats with neuropathic pain.

METHODSThe neuropathic pain model was established by chronic constriction injury (CCI) 7 days before electrophysiological-recording. The rat DRG neurons were enzymatically dissociated. Whole-cell patch clamp technique was used to record GABA-activated currents. The changes of currents of injured side and opposite side were expected to compare with control group.

RESULTS(1) The currents of injured side of CCI group were notablely decreased compared with control group (GABA concentration, 0.1-1000 micromol/L). (2) By the contrast, opposite side currents of CCI group increased significantly compared with those in injured side and control group (GABA concentration, 0.01-1000 micromol/L).

CONCLUSIONThe data indicates that the chronic constriction injury change both the function of GABAA receptors of injury side and opposite side. The decrease of pre-synaptic inhibition of GABA may be the possible reason of neuropathic pain.

Animals ; Cell Separation ; Constriction ; Ganglia, Spinal ; pathology ; physiopathology ; Male ; Neuralgia ; etiology ; physiopathology ; Neurons ; metabolism ; physiology ; Patch-Clamp Techniques ; Rats ; Rats, Sprague-Dawley ; Receptors, GABA-A ; metabolism ; physiology ; Sciatic Nerve ; injuries