Gregory Dussor

Unmasking the tonic-aversive state in neuropathic pain

Tonic pain has been difficult to demonstrate in animals. Because relief of pain is rewarding, analgesic agents that are not rewarding in the absence of pain should become rewarding only when there is ongoing pain. We used conditioned place preference to concomitantly determine the presence of tonic pain in rats and the efficacy of agents that relieve it. This provides a new approach for investigating tonic pain in animals and for evaluating the analgesic effects of drugs.

Engagement of descending inhibition from the rostral ventromedial medulla protects against chronic neuropathic pain

Summary A rat population with variable responses to nerve injury indicated that activation of descending inhibition with a spinal noradrenergic component prevents development of neuropathic pain. ABSTRACT 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 dorsal root ganglion or spinal neuropathic markers after 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 (ie, OFF) and excitatory (ie, 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 nonallodynic HZ rats. Similarly, RVM U69,593 (kappa opioid agonist) or blockade of spinal α2 adrenergic receptors precipitated allodynia in previously nonallodynic 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.

IL-6- and NGF-Induced Rapid Control of Protein Synthesis and Nociceptive Plasticity via Convergent Signaling to the eIF4F Complex

Despite the emergence of translational control pathways as mediators of nociceptive sensitization, effector molecules and mechanisms responsible for modulating activity in these pathways in pain conditions are largely unknown. We demonstrate that two major algogens, the cytokine interleukin 6 (IL-6) and the neurotrophin nerve growth factor (NGF), which are intimately linked to nociceptive plasticity across preclinical models and human pain conditions, signal primarily through two distinct pathways to enhance translation in sensory neurons by converging onto the eukaryotic initiation factor (eIF) eIF4F complex. We directly demonstrate that the net result of IL-6 and NGF signaling is an enhancement of eIF4F complex formation and an induction of nascent protein synthesis in primary afferent neurons and their axons. Moreover, IL-6- and NGF-induced mechanical nociceptive plasticity is blocked by inhibitors of general and cap-dependent protein synthesis. These results establish IL-6- and NGF-mediated cap-dependent translation of local proteins as a new model for nociceptive plasticity.

Triptan-induced latent sensitization: a possible basis for medication overuse headache.

Identification of the neural mechanisms underlying medication overuse headache resulting from triptans.

A phenotypically restricted set of primary afferent nerve fibers innervate the bone versus skin: therapeutic opportunity for treating skeletal pain.

Although musculoskeletal pain is one of the most common causes of chronic pain and physical disability in both developing and developed countries, relatively little is known about the nerve fibers and mechanisms that drive skeletal pain. Small diameter sensory nerve fibers, most of which are C-fiber nociceptors, can be separated into two broad populations: the peptide-rich and peptide-poor nerve fibers. Peptide-rich nerve fibers express substance P (SP) and calcitonin gene-related peptide (CGRP). In contrast, the peptide-poor nerve fibers bind to isolectin B4 (IB(4)) and express the purinergic receptor P(2)X(3) and Mas-related G protein-coupled receptor member d (Mrgprd). In the present report, we used mice in which the Mrgprd(+) nerve fibers express genetically encoded axonal tracers to determine the peptide-rich and peptide-poor sensory nerve fibers that innervate the glabrous skin of the hindpaw as compared to the bone marrow, mineralized bone and periosteum of the femur. Whereas the skin is richly innervated by CGRP(+), SP(+), P(2)X(3)(+) and Mrgprd(+) sensory nerve fibers, the bone marrow, mineralized bone and periosteum receive a significant innervation by SP(+) and CGRP(+), but not Mrgprd(+) and P(2)X(3)(+) nerve fibers. This lack of redundancy in the populations of C-fibers that innervate the bone may present a unique therapeutic opportunity for targeting skeletal pain as the peptide-rich and peptide-poor sensory nerve fibers generally express a different repertoire of receptors and channels to detect noxious stimuli. Thus, therapies that target the specific types of C-nerve fibers that innervate the bone may be uniquely effective in attenuating skeletal pain as compared to skin pain.

Dural afferents express acid-sensing ion channels: a role for decreased meningeal pH in migraine headache

&NA; Migraine headache is one of the most common neurological disorders. The pathological conditions that directly initiate afferent pain signaling are poorly understood. In trigeminal neurons retrogradely labeled from the cranial meninges, we have recorded pH‐evoked currents using whole‐cell patch‐clamp electrophysiology. Approximately 80% of dural‐afferent neurons responded to a pH 6.0 application with a rapidly activating and rapidly desensitizing ASIC‐like current that often exceeded 20 nA in amplitude. Inward currents were observed in response to a wide range of pH values and 30% of the neurons exhibited inward currents at pH 7.1. These currents led to action potentials in 53%, 30% and 7% of the dural afferents at pH 6.8, 6.9 and 7.0, respectively. Small decreases in extracellular pH were also able to generate sustained window currents and sustained membrane depolarizations. Amiloride, a non‐specific blocker of ASIC channels, inhibited the peak currents evoked upon application of decreased pH while no inhibition was observed upon application of TRPV1 antagonists. The desensitization time constant of pH 6.0‐evoked currents in the majority of dural afferents was less than 500 ms which is consistent with that reported for ASIC3 homomeric or heteromeric channels. Finally, application of pH 5.0 synthetic‐interstitial fluid to the dura produced significant decreases in facial and hind‐paw withdrawal threshold, an effect blocked by amiloride but not TRPV1 antagonists, suggesting that ASIC activation produces migraine‐related behavior in vivo. These data provide a cellular mechanism by which decreased pH in the meninges following ischemic or inflammatory events directly excites afferent pain‐sensing neurons potentially contributing to migraine headache.

Afferent Drive Elicits Ongoing Pain in a Model of Advanced Osteoarthritis

Summary Monosodium iodoacetate (MIA)‐induced ongoing pain depends on input from the joint; blockade of TRPV1 and TRPA1 channels fails to block MIA‐induced ongoing pain. Abstract Osteoarthritis (OA) is a chronic condition characterized by pain during joint movement. Additionally, patients with advanced disease experience pain at rest (ie, ongoing pain) that is generally resistant to nonsteroidal antiinflammatory drugs. Injection of monosodium iodoacetate (MIA) into the intraarticular space of the rodent knee is a well‐established model of OA that elicits weight‐bearing asymmetry and referred tactile and thermal hypersensitivity. Whether ongoing pain is present in this model is unknown. Additionally, the possible relationship of ongoing pain to MIA dose is not known. MIA produced weight asymmetry, joint osteolysis, and cartilage erosion across a range of doses (1, 3, and 4.8 mg). However, only rats treated with the highest dose of MIA showed conditioned place preference to a context paired with intraarticular lidocaine, indicating relief from ongoing pain. Diclofenac blocked the MIA‐induced weight asymmetry but failed to block MIA‐induced ongoing pain. Systemic AMG9810, a transient receptor potential V1 channel (TRPV1) antagonist, effectively blocked thermal hypersensitivity, but failed to block high‐dose MIA‐induced weight asymmetry or ongoing pain. Additionally, systemic or intraarticular HC030031, a TRPA1 antagonist, failed to block high‐dose MIA‐induced weight asymmetry or ongoing pain. Our studies suggest that a high dose of intraarticular MIA induces ongoing pain originating from the site of injury that is dependent on afferent fiber activity but apparently independent of TRPV1 or TRPA1 activation. Identification of mechanisms driving ongoing pain may enable development of improved treatments for patients with severe OA pain and diminish the need for joint replacement surgery.

Capturing the aversive state of cephalic pain preclinically

Preclinical evaluation of headache by behavioral assessment of reward from pain relief.

Cutaneous Sensory Neurons Expressing the Mrgprd Receptor Sense Extracellular ATP and Are Putative Nociceptors

Sensory neurons expressing the Mrgprd receptor are known to innervate the outermost living layer of the epidermis, the stratum granulosum. The sensory modality that these neurons signal and the stimulus that they respond to are not established, although immunocytochemical data suggest they could be nonpeptidergic nociceptors. Using patch clamp of dissociated mouse dorsal root ganglion (DRG) neurons, the present study demonstrates that Mrgprd+ neurons have several properties typical of nociceptors: long-duration action potentials, TTX-resistant Na(+) current, and Ca(2+) currents that are inhibited by mu opioids. Remarkably, Mrgprd+ neurons respond almost exclusively to extracellular ATP with currents similar to homomeric P2X3 receptors. They show little or no sensitivity to other putative nociceptive agonists, including capsaicin, cinnamaldehyde, menthol, pH 6.0, or glutamate. These properties, together with selective innervation of the stratum granulosum, indicate that Mrgprd+ neurons are nociceptors in the outer epidermis and may respond indirectly to external stimuli by detecting ATP release in the skin.

Contribution of PKMζ-dependent and independent amplification to components of experimental neuropathic pain

TOC summary PKMζ‐dependent amplification contributes to nerve injury‐induced aversiveness within the rostral anterior cingulate cortex and to evoked, but not spontaneous, pain in the spinal cord. ABSTRACT Injuries can induce adaptations in pain processing that result in amplification of signaling. One mechanism may be analogous to long‐term potentiation and involve the atypical protein kinase C, PKMζ. The possible contribution of PKMζ‐dependent and independent amplification mechanisms to experimental neuropathic pain was explored in rats with spinal nerve ligation (SNL) injury. SNL increased p‐PKMζ in the rostral anterior cingulate cortex (rACC), a site that mediates, in part, the unpleasant aspects of pain. Inhibition of PKMζ within the rACC by a single administration of ζ‐pseudosubstrate inhibitory peptide (ZIP) reversed SNL‐induced aversiveness within 24 hours, whereas N‐methyl‐D‐aspartate receptor blockade with MK‐801 had no effects. The SNL‐induced aversive state (reflecting “spontaneous” pain), was re‐established in a time‐dependent manner, with full recovery observed 7 days post‐ZIP administration. Neither rACC ZIP nor MK‐801 altered evoked responses. In contrast, spinal ZIP or MK‐801, but not scrambled peptide, transiently reversed evoked hypersensitivity, but had no effect on nerve injury‐induced spontaneous pain. PKMζ phosphorylation was not altered by SNL in the spinal dorsal horn. These data suggest that amplification mechanisms contribute to different aspects of neuropathic pain at different levels of the neuraxis. Thus, PKMζ‐dependent amplification contributes to nerve injury‐induced aversiveness within the rACC. Moreover, unlike mechanisms maintaining memory, the consequences of PKMζ inhibition within the rACC are not permanent in neuropathic pain, possibly reflecting the re‐establishment of amplification mechanisms by ongoing activity of injured nerves. In the spinal cord, however, both PKMζ‐dependent and independent mechanisms contribute to amplification of evoked responses, but apparently not spontaneous pain.