The underlying mechanisms of neuropathic pain are poorly understood, and existing treatments are mostly ineffective. We recently demonstrated that antisense mediated "knock-down" of the sodium channel isoform, Na(V)1.8, reverses neuropathic pain behavior after L5/L6 spinal nerve ligation (SNL), implicating a critical functional role of Na(V)1.8 in the neuropathic state. Here we have investigated mechanisms through which Na(V)1.8 contributes to the expression of experimental neuropathic pain. Na(V)1.8 does not appear to contribute to neuropathic pain through an action in injured afferents because the channel is functionally downregulated in the cell bodies of injured neurons and does not redistribute to injured terminals. Although there was little change in Na(V)1.8 protein or functional channels in the cell bodies of uninjured neurons in L4 ganglia, there was a striking increase in Na(V)1.8 immunoreactivity along the sciatic nerve. The distribution of Na(V)1.8 reflected predominantly the presence of functional channels in unmyelinated axons. The C-fiber component of the sciatic nerve compound action potential (CAP) was resistant (>40%) to 100 microm TTX after SNL, whereas both A- and C-fiber components of sciatic nerve CAP were blocked (>90%) by 100 microm TTX in sham-operated rats or the contralateral sciatic nerve of SNL rats. Attenuating expression of Na(V)1.8 with antisense oligodeoxynucleotides prevented the redistribution of Na(V)1.8 in the sciatic nerve and reversed neuropathic pain. These observations suggest that aberrant activity in uninjured C-fibers is a necessary component of pain associated with partial nerve injury. They also suggest that blocking Na(V)1.8 would be an effective treatment of neuropathic pain.

Objective Identification of the neural mechanisms underlying medication overuse headache resulting from triptans. Methods Triptans were administered systemically to rats by repeated intermittent injections or by continuous infusion over 6 days. Periorbital and hind paw sensory thresholds were measured to detect cutaneous allodynia. Immunofluorescent histochemistry was employed to detect changes in peptidic neurotransmitter expression in identified dural afferents. Enzyme-linked immunoabsorbent assay was used to measure calcitonin gene-related peptide (CGRP) levels in blood. Results Sustained or repeated administration of triptans to rats elicited time-dependent and reversible cutaneous tactile allodynia that was maintained throughout and transiently after drug delivery. Triptan administration increased labeling for CGRP in identified trigeminal dural afferents that persisted long after discontinuation of triptan exposure. Two weeks after triptan exposure, when sensory thresholds returned to baseline levels, rats showed enhanced cutaneous allodynia and increased CGRP in the blood following challenge with a nitric oxide donor. Triptan treatment thus induces a state of latent sensitization characterized by persistent pronociceptive neural adaptations in dural afferents and enhanced responses to an established trigger of migraine headache in humans. Interpretation Triptans represent the treatment of choice for moderate and severe migraine headaches. However, triptan overuse can lead to an increased frequency of migraine headache. Overuse of these medications could induce neural adaptations that result in a state of latent sensitization, which might increase sensitivity to migraine triggers. The latent sensitization could provide a mechanistic basis for the transformation of migraine to medication overuse headache.

Paradoxical opioid-induced pain has been demonstrated repeatedly in humans and animals. The mechanisms of such pain are unknown but may relate to opioid-induced activation of descending pain facilitatory systems and enhanced expression and pronociceptive actions of spinal dynorphin. Here, the possibility that these opioid-induced central changes might mediate increased excitability to the spinal cord was tested. Tactile and thermal hypersensitivity was observed at 7, but not 1, days after subcutaneous morphine pellet implantation; placebo pellets produced no effects. Basal and capsaicin-evoked release of calcitonin gene-related peptide (CGRP) was measured in minced spinal tissues taken from naive rats or rats on post-pellet days 1 and 7. The content and evoked release of CGRP were significantly increased in tissues from morphine-exposed rats at 7, but not 1, days after implantation. Morphine increased spinal dynorphin content on day 7 in rats with sham bilateral lesions of the dorsolateral funiculus (DLF) but not in rats with DLF lesions. Pharmacological application of dynorphin A(2-13), a non-opioid fragment, to tissues from naive rats enhanced the evoked release of CGRP. Enhanced evoked release of CGRP from morphine-pelleted rats was blocked by dynorphin antiserum or by previous lesions of the DLF. Sustained morphine induces plasticity in both primary afferents and spinal cord, including increased CGRP and dynorphin content. Morphine-induced elevation of spinal dynorphin content depends on descending influences and enhances stimulated CGRP release. Enhanced transmitter release may allow increased stimulus-evoked spinal excitation, which is likely to be critical for opioid-induced paradoxical pain. Such pain may manifest behaviorally as antinociceptive tolerance.

The clinical management of neuropathic pain is particularly challenging. Current therapies for neuropathic pain modulate nerve impulse propagation or synaptic transmission; these therapies are of limited benefit and have undesirable side effects. Injuries to peripheral nerves result in a host of pathophysiological changes associated with the sustained expression of abnormal pain. Here we show that systemic, intermittent administration of artemin produces dose- and time-related reversal of nerve injury-induced pain behavior, together with partial to complete normalization of multiple morphological and neurochemical features of the injury state. These effects of artemin were sustained for at least 28 days. Higher doses of artemin than those completely reversing experimental neuropathic pain did not elicit sensory or motor abnormalities. Our results indicate that the behavioral symptoms of neuropathic pain states can be treated successfully, and that partial to complete reversal of associated morphological and neurochemical changes is achievable with artemin.

A puzzling observation is why peripheral nerve injury results in chronic pain in some, but not all, patients. We explored potential mechanisms that may prevent the expression of chronic pain. Sprague-Dawley (SD) or Holtzman (HZ) rats showed no differences in baseline sensory thresholds or responses to inflammatory stimuli. However, spinal nerve ligation (SNL)-induced tactile allodynia occurred in approximately 85% of SD and 50% of HZ rats, respectively. No apparent differences were observed in a survey of DRG or spinal “neuropathic markers” following SNL regardless of allodynic phenotype. SNL-induced allodynia was reversed by administration of lidocaine within the rostral ventromedial medulla (RVM), a site that integrates descending pain modulation via pain inhibitory (i.e., OFF) and excitatory (i.e., ON) cells. However, in SD or HZ rats with SNL but without allodynia, RVM lidocaine precipitated allodynia. Additionally, RVM lidocaine produced conditioned place preference in allodynic SD or HZ rats but conditioned place aversion in non-allodynic HZ rats. Similarly, RVM U69,593 (kappa opioid agonist) or blockade of spinal α2 adrenergic receptors precipitated allodynia in previously non-allodynic HZ rats with SNL. All rats showed an equivalent first phase formalin responses. However, HZ rats had reduced second phase formalin behaviors along with fewer RVM OFF cell pauses and RVM ON cell bursts. Thus, expression of nerve-injury induced pain may ultimately depend on descending modulation. Engagement of descending inhibition protects in the transition from acute to chronic pain. These unexpected findings might provide a mechanistic explanation for medications that engage descending inhibition or mimic its consequences.