In humans, trauma to a peripheral nerve may be followed by chronic pain syndromes which are only relieved by blockade of the effects of sympathetic impulse traffic. It is presumed that, after the lesion, noradrenaline released by activity of sympathetic postganglionic axons excites primary afferent neurons by activating alpha-adrenoceptors, generating signals that enter the 'pain pathways' of the central nervous system. The site of coupling is unclear. In some patients local anaesthesia of the relevant peripheral nerve does not alleviate pain, implying that ectopic impulses arise either within the central nervous system, or in proximal parts of the primary afferent neurons. In experimentally lesioned rats, activity can originate within the dorsal root ganglia. Here we report that, after sciatic nerve ligation, noradrenergic perivascular axons in rats sprout into dorsal root ganglia and form basket-like structures around large-diameter axotomized sensory neurons; sympathetic stimulation can activate such neurons repetitively. These unusual connections provide a possible origin for abnormal discharge following peripheral nerve damage. Further, in contrast to the sprouting of intact nerve terminals into nearby denervated effector tissues in skin, muscle, sympathetic ganglia and sweat glands, the axons sprout into a target which has not been partially denervated.

Osteoarthritis is a painful and disabling disease that affects millions of patients. Its aetiology is largely unknown, but is most likely multi-factorial. Osteoarthritis poses a dilemma: it often begins attacking different joint tissues long before middle age, but cannot be diagnosed until it becomes symptomatic decades later, at which point structural alterations are already quite advanced. In this review, osteoarthritis is considered as a disease of the whole joint that may result from multiple pathophysiological mechanisms, one of which is the dysregulation of lipid homeostasis. No proven disease-modifying therapy exists for osteoarthritis and current treatment options for chronic osteoarthritic pain are insufficient, but new pharmacotherapeutic options are emerging.

We examined the relation between ectopic afferent firing and tactile allodynia in the Chung model of neuropathic pain. Transection of the L5 spinal nerve in rats triggered a sharp, four- to six-fold increase in the spontaneous ectopic discharge recorded in vivo in sensory axons in the ipsilateral L5 dorsal root (DR). The increase, which was not yet apparent 16 h postoperatively, was complete by 24 h. This indicates rapid modification of the electrical properties of the neurons. Only A-neurons, primarily rapidly conducting A-neurons, contributed to the discharge. No spontaneously active C-neurons were encountered. Tactile allodynia in hindlimb skin emerged during precisely the same time window after spinal nerve section as the ectopia, suggesting that ectopic activity in injured myelinated afferents can trigger central sensitization, the mechanism believed to be responsible for tactile allodynia in the Chung model. Most of the spike activity originated in the somata of axotomized DRG neurons; the spinal nerve end neuroma accounted for only a quarter of the overall ectopic barrage. Intracellular recordings from afferent neuron somata in excised DRGs in vitro revealed changes in excitability that closely paralleled those seen in the DR axon recordings in vivo. Corresponding changes in biophysical characteristics of the axotomized neurons were catalogued. Axotomy carried out at a distance from the DRG, in the mid-portion of the sciatic nerve, also triggered increased afferent excitability. However, this increase occurred at a later time following axotomy, and the relative contribution of DRG neuronal somata, as opposed to neuroma endings, was smaller. Axotomy triggers a wide variety of changes in the neurochemistry and physiology of primary afferent neurons. Investigators studying DRG neurons in culture need to be alert to the rapidity with which axotomy, an inevitable consequence of DRG excision and dissociation, alters key properties of these neurons. Our identification of a specific population of neurons whose firing properties change suddenly and synchronously following axotomy, and whose activity is associated with tactile allodynia, provides a powerful vehicle for defining the specific cascade of cellular and molecular events that underlie neuropathic pain.

Abnormal afferent discharge originating at ectopic sites in injured primary sensory neurons is thought to be an important generator of paraesthesias, dysaesthesias, and chronic neuropathic pain. We report here that the ability of these neurons to sustain repetitive discharge depends on intrinsic resonant properties of the cell membrane and that the prevalence of this characteristic increases after nerve injury. Recording from primary sensory neurons in excised rat dorsal root ganglia, we found that some cells show subthreshold oscillations in their membrane potential. The amplitude, frequency, and coherence of these oscillations were voltage sensitive. Oscillations gave rise to action potentials when they reached threshold. Indeed, the presence of oscillations proved to be a necessary condition for sustained spiking both at resting membrane potential and on depolarization; neurons without them were incapable of sustained discharge even on deep depolarization. Previous nerve injury increased the proportion of neurons sampled that had subthreshold oscillations, and hence the proportion that generated ectopic spike discharge. Oscillatory behavior and ectopic spiking were eliminated by [Na(+)](o) substitution or bath application of lidocaine or tetrodotoxin (TTX), under conditions that preserved axonal spike propagation. This suggests that a TTX-sensitive Na(+) conductance contributes to the oscillations. Selective pharmacological suppression of subthreshold oscillations may offer a means of controlling neuropathic paraesthesias and pain without blocking afferent nerve conduction.

Osteoarthritis (OA) is the biggest unmet medical need among the many musculoskeletal conditions and the most common form of arthritis. It is a major cause of disability and impaired quality of life in the elderly. We review several ambitious but failed attempts to develop joint structure-modifying treatments for OA. Insights gleaned from these attempts suggest that these failures arose from unrealistic hypotheses, sub-optimal selection of patient populations or drug dose, and/or inadequate sensitivity of the trial endpoints. The long list of failures has prompted a paradigm shift in OA drug development with redirection of attention to: (1) consideration of the benefits of localized vs systemic pharmacological agents, as indicated by the increasing number of intra-articularly administered compounds entering clinical development; (2) recognition of OA as a complex disease with multiple phenotypes, that may each require somewhat different approaches for optimizing treatment; and (3) trial enhancements based on guidance regarding biomarkers provided by regulatory agencies, such as the Food and Drug Administration (FDA), that could be harnessed to help turn failures into successes.

Primary sensory neurons with myelinated axons were examined in vitro in excised whole lumbar dorsal root ganglia (DRGs) taken from adult rats up to 9 days after tight ligation and transection of the L(5) spinal nerve (Chung model of neuropathic pain). Properties of subthreshold membrane potential oscillations, and of repetitive spike discharge, were examined. About 5% of the DRG neurons sampled in control DRGs exhibited high-frequency, subthreshold sinusoidal oscillations in their membrane potential at rest (V(r)), and an additional 4.4% developed such oscillations on depolarization. Virtually all had noninflected action potentials (A(0) neurons). Amplitude and frequency of subthreshold oscillations were voltage sensitive. A(0) neurons with oscillations at V(r) appear to constitute a population distinct from A(0) neurons that oscillate only on depolarization. Axotomy triggered a significant increase in the proportion of neurons exhibiting subthreshold oscillations both at V(r) and on depolarization. This change occurred within a narrow time window 16-24 h postoperative. Axotomy also shifted the membrane potential at which oscillation amplitude was maximal to more negative (hyperpolarized) values, and lowered oscillation frequency at any given membrane potential. Most neurons that had oscillations at V(r), or that developed them on depolarization, began to fire repetitively when further depolarized. Spikes were triggered by the depolarizing phase of oscillatory sinusoids. Neurons that did not develop subthreshold oscillations never discharged repetitively and rarely fired more than a single spike or a short burst, on step depolarization. The most prominent spike waveform parameters distinguishing neurons capable of generating subthreshold oscillations, and hence repetitive firing, was their brief postspike afterhyperpolarization (AHP) and their low single-spike threshold. Neurons that oscillated at V(r) tended to have a more prolonged spike, with slower rise- and fall-time kinetics, and lower spike threshold, than cells that oscillated only on depolarization. The main effects of axotomy were to increase spike duration, slow rise- and fall-time kinetics, and reduce single-spike threshold. Tactile allodynia following spinal nerve injury is thought to result from central amplification ("central sensitization") of afferent signals entering the spinal cord from residual intact afferents. The central sensitization, in turn, is thought to be triggered and maintained in the Chung model by ectopic firing originating in the axotomized afferent neurons. Axotomy by spinal nerve injury enhances subthreshold membrane potential oscillations in DRG neurons, augments ectopic discharge, and hence precipitates neuropathic pain.

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Heat sensitivity shows considerable functional variability in humans and laboratory animals, and is fundamental to inflammatory and possibly neuropathic pain. In the mouse, at least, much of this variability is genetic because inbred strains differ robustly in their behavioral sensitivity to noxious heat. These strain differences are shown here to reflect differential responsiveness of primary afferent thermal nociceptors to heat stimuli. We further present convergent behavioral and electrophysiological evidence that the variable responses to noxious heat are due to strain-dependence of CGRP expression and sensitivity. Strain differences in behavioral response to noxious heat could be abolished by peripheral injection of CGRP, blockade of cutaneous and spinal CGRP receptors, or long-term inactivation of CGRP with a CGRP-binding Spiegelmer. Linkage mapping supports the contention that the genetic variant determining variable heat pain sensitivity across mouse strains affects the expression of the Calca gene that codes for CGRP␣.calcitonin gene-related peptide ͉ genetic ͉ Calca ͉ nociceptors ͉ pain H umans display wide individual variability in sensitivity to pain.Although the relative importance of genes versus experience in human pain perception is unclear, recent studies have shown that mouse strains display large differences in behavioral pain sensitivity that are heritable (1). These same studies revealed genetic correlations between baseline thermal nociception and the hypersensitivity states associated with inflammatory and neuropathic pain (2). Of the strains examined, AKR and C57BL͞6 mice displayed the largest and most consistent differences in several different assays of thermal nociception, with AKR being much less sensitive than C57BL͞6. In contrast, AKR mice exhibit more robust heat hyperalgesia after inflammatory or nerve injury (1). Despite our considerable knowledge of the behavioral ''phenomics'' of baseline heat pain and hyperalgesia, there are almost no published data regarding the underlying cellular or molecular mechanisms. Here we show that the observed strain differences in response to thermal stimulation are caused by corresponding differences in the functioning of primary afferent nociceptors. The differences in nociceptor sensitivity, in turn, are caused by the presence of and sensitivity to the neuropeptide calcitonin gene-related polypeptide (CGRP). Finally, linkage mapping revealed a candidate gene likely responsible for the strain difference: Calca, the gene encoding CGRP␣.CGRP␣ is a secretory neuropeptide released from thin nerve fibers at their peripheral and central terminals, which is thought to contribute importantly to neurogenic inflammation in the skin and to central sensitization in the spinal cord (3-6). CGRP acts through a G s protein-coupled receptor complex to activate cAMPdependent protein kinase (PKA). PKA, via the transcription factor cAMP response element-binding protein, enhances expression of pronociceptive genes including the Calca gene itself (7-9). Moreover, many...