Proenkephalin A gene products activate a new family of sensory neuron--specific GPCRs.

Several peptide fragments are produced by proteolytic cleavage of the opioid peptide precursor proenkephalin A, and among these are a number of enkephalin fragments, in particular bovine adrenal medulla peptide 22 (BAM22). These peptide products have been implicated in diverse biological functions, including analgesia. We have cloned a newly identified family of 'orphan' G protein--coupled receptors (GPCRs) and demonstrate that BAM22 and a number of its fragments bind to and activate these receptors with nanomolar affinities. This family of GPCRs is uniquely localized in the human and rat small sensory neuron, and we called this family the sensory neuron--specific G protein--coupled receptors (SNSRs). Receptors of the SNSR family are distinct from the traditional opioid receptors in their insensitivity to the classical opioid antagonist naloxone and poor activation by opioid ligands. The unique localization of SNSRs and their activation by proenkephalin A peptide fragments indicate a possible function for SNSRs in sensory neuron regulation and in the modulation of nociception.

Antinociceptive activity of the bradykinin B1 and B2 receptor antagonists, des-Arg9, [Leu8]-BK and HOE 140, in two models of persistent hyperalgesia in the rat.

There has been recent evidence linking bradykinin (BK) receptors with inflammation. This study has investigated the involvement of BK receptors in two models of persistent inflammatory hyperalgesia in rats. In a Freund's adjuvant-induced hyperalgesia model and an ultraviolet (UV)-induced hyperalgesia model in rats the specific B2 antagonist, D-Arg[Hyp3, Thi5, D-Tic7, Oic8]-BK (HOE 140), was either ineffective or weakly active in reversing hyperalgesia. The specific B1 antagonist, des-Arg9, [Leu8]-BK, was effective in reversing or preventing the development of hyperalgesia in both Freund's adjuvant-induced hyperalgesia and UV-induced hyperalgesia. The B1 agonist, des-Arg9-BK, produced a small exacerbation of hyperalgesia in both models. Data suggest that in persistent inflammatory conditions in the rat bradykinin B1 receptors are involved in the accompanying hyperalgesia.

A pro-nociceptive role of neuromedin U in adult mice.

Although the neuropeptide neuromedin U (NMU) was first isolated from the spinal cord, its actions in this site are unknown. The recent identification of the NMU receptor subtype 2 (NMU2R) in the spinal cord has increased the interest in investigating the role of NMU in this part of the central nervous system. Here, we report a novel function for NMU in spinal nociception in the mouse. Systemic perfusion of NMU (rat, NMU-23) dose-dependently (0.2, 0.5, 1, and 2.5 microM) potentiated both the background activity and noxious pinch-evoked response of nociceptive or wide dynamic range, but not non-nociceptive, dorsal horn neurons. At 2.5 microM, NMU-23 increased the total background activity from 154+/-34 to 1374+/-260 spikes/160 s (P<0.005, n=28) and increased the evoked nociceptive response by 185+/-50% (P<0.01, n=13). Intrathecal administration of NMU-23 (0.4, 1.1, and 3.8 nmol/10 microl) dose-dependently decreased thermal withdrawal latencies and produced a morphine-sensitive behavioral response. These electrophysiological and behavioral results suggest that NMU may be a novel physiological regulator in spinal nociceptive transmission and processing.

Intrathecal nerve growth factor restores opioid effectiveness in an animal model of neuropathic pain.

It is without dispute that the treatment of neuropathic pain is an area of largely unmet medical need. Available analgesics, such as morphine, either have minimal effects in neuropathic pain patients, or are not always well tolerated due to concurrent adverse effects. The chronicity of neuropathic pain is thought to be related to many neurochemical changes in the dorsal root ganglia (DRG) and spinal cord, including a reduction in the retrograde transport of nerve growth factor (NGF). In this study, we have determined the ability of chronic intrathecal (i.t.) infusion of NGF to reverse neuropathic pain symptoms and to restore morphine's effectiveness in an animal model of neuropathic pain. Seven days after sciatic nerve constriction injury, NGF was administered to the spinal cord by continuous infusion (125 ng/microl/h) via osmotic pumps attached to chronically implanted i.t. catheters. Spinal infusion of NGF did not affect the expression of tactile allodynia or thermal (hot) hyperalgesia in neuropathic rats, although it significantly increased cold water responses frequency at day 14. Following infusion of vehicle, i.t. morphine (20 microg) was ineffective in altering somatosensory thresholds in neuropathic rats. In contrast, morphine substantially attenuated the neuropathy-induced warm and cold hyperalgesia, as well as tactile allodynia, in neuropathic rats chronically infused with i.t. NGF. In addition, we demonstrate that i.t. morphine-induced antinociception was augmented by a cholecystokinin (CCK) antagonist in animals chronically infused with i.t. antibodies directed against NGF. We hypothesize that NGF is critical in maintaining neurochemical homeostasis in the spinal cord of nociceptive neurons, and that supplementation may be beneficial in restoring and/or maintaining opioid analgesia in chronic pain conditions resulting from traumatic nerve injury.

Novel G protein-coupled receptors as pain targets.

G protein-coupled receptors (GPCRs) and their ligands play a number of important roles in the modulation of acute and chronic pain. Indeed, opioid and cannabinoid ligands are of established therapeutic value for pain management, and further exploitation of the specific GPCR subtypes (delta-opioid, CB1 and CB2) for these ligands may yield more selective, potent analgesics with favorable side effects. More recent identification of a number of other GPCRs involved in pain pathways (eg, sensory neuron specific receptors) and selective ligands that modulate pain transmission, has highlighted further therapeutic opportunities. A further challenge to understanding pain modulation and an additional dimension for targeting analgesia is the discovery of GPCR heteromerization and accessory and regulatory proteins, such as regulator of G protein-signaling proteins, involved in expression and regulation of GPCR.

Enhanced thermal antinociceptive potency and anti-allodynic effects of morphine following spinal administration of endotoxin.

Recently, an animal model of central inflammation characterized by widespread cutaneous hyperalgesia and allodynia following intracerebroventricular (i.c.v.) administration of lipopolysaccharide (LPS) was described. In the present study, we demonstrate that central administration of LPS via intrathecal (i.t.) injection produces bilateral tactile allodynia and thermal hyperalgesia in the rat. Also, the effects of morphine-induced antinociception were determined in this model. Here we demonstrate enhanced thermal antinociceptive potency of i.t. morphine in LPS-treated rats compared to controls. Intrathecal morphine was also effective in alleviating the tactile allodynia induced by LPS. Both the antinociceptive and anti-allodynic effects produced by i.t. morphine were completely antagonized by pretreatment with subcutaneous naloxone (1 mg x kg(-1)). This study demonstrates the presence of both heat hyperalgesia and mechanical allodynia following central administration of LPS, and an increased antinociceptive potency of i.t. morphine in this model.

Antisense oligonucleotide knockdown of mGluR1 alleviates hyperalgesia and allodynia associated with chronic inflammation.

Chronic inflammation induced by injection of complete Freund's adjuvant (CFA) into one hindpaw elicits thermal hyperalgesia and mechanical allodynia in the injected paw. Metabotropic glutamate receptors (mGluRs) have been implicated in dorsal horn neuronal nociceptive responses and pain associated with short-term inflammation. The goal of the present study was to assess the role of mGluR1 in the hyperalgesia and allodynia associated with the CFA model of chronic inflammation. Here we show that antisense (AS) oligonucleotide knockdown of spinal mGluR1 attenuates thermal hyperalgesia and mechanical allodynia in rats injected with CFA in one hindpaw. When intrathecal infusion of mGluR1 AS oligonucleotide (50 microg/day) began prior to CFA injection, mechanical allodynia was attenuated from Days 1 to 8 following CFA injection, whereas heat hyperalgesia was attenuated on Day 1 and then from Days 4 to 8. When intrathecal infusion of mGluR1 AS oligonucleotide was begun 2 days after CFA injection, both mechanical allodynia and heat hyperalgesia were attenuated at all time points following the oligonucleotide infusion. Thus, the present data suggest a role for mGluR1 in persistent inflammatory nociception.

Future pharmacologic management of neuropathic pain.

Neuropathic pain therapy remains enormously challenging despite the increases in knowledge of pain etiology and mechanisms drawn from animal studies. Mechanism-based discovery underlies key approaches toward reduction of peripheral and central hyperexcitability. These include a number of poorly validated molecular targets, such as ion channels, G-protein coupled receptors, purinergic receptors, and chemokine receptors, as well as downstream regulators of protein phosphorylation. Improvement in translating these approaches into the development of drugs for use in the pain clinic remains a significant but surmountable challenge.

New horizons in pharmacologic treatment for rheumatic disease pain.

Chronic pain is the major concern for patients with rheumatic diseases, such as low back pain, osteoarthritis, and rheumatoid arthritis, but current therapies are suboptimal. Animal models and emerging clinical data indicate that there is a complex spectrum of neurologic changes, manifesting both nociceptive and neuropathic pain, which are driven by joint pathophysiology and abnormal excitability in peripheral and central pain pathways. A variety of mechanisms and molecular drivers have been identified that can support future segmentation of musculoskeletal pain patients. Emerging therapies are directed to targeting inflammatory mediators, ligand and voltage regulated ion channels, as well as increasing inhibition through monoaminergic modulation. Finally, neurotrophic abnormalities may be restored through the modulation of specific neurotrophins. These developments are supported by increasing emphasis on the clinical understanding of the neurologic changes in pain patients to enable confident translation to clinical application.

Osteoarthritic pain: a review of current, theoretical and emerging therapeutics.

BACKGROUND: Despite exciting progress and growth in the understanding of molecular and cellular mechanisms of chronic pain, osteoarthritis (OA) pain remains a challenging clinical entity to treat. There is an emerging diversity of algogenic mechanisms suggesting heterogeneity in pain aetiology in the OA patient population. OBJECTIVE/METHODS: This review article summarises key issues in existing therapies for OA pain and highlights the emerging compounds in early and late development. It also highlights where tolerability may be a concern, especially in the older populations in which treatment interactions for co-morbid conditions may further narrow therapeutic index. Importantly, the authors also examine the diversity of biology that underpins OA pain and highlight the opportunities for the future. RESULTS/CONCLUSIONS: Many emerging therapies are presently in proof-of-concept clinical testing for treatment of OA. A growing understanding of the heterogeneity in the OA patient population, will challenge the ability to accurately understand observed efficacy or safety signals in these relatively small trials and how they may titrate to a broader patient population. We may need to wait several more years to understand whether the need for a differentiated therapy demanded by patients, payors and physicians alike, will be met.

Arthritis and pain. Future targets to control osteoarthritis pain.

Clinical presentation of osteoarthritis (OA) is dominated by pain during joint use and at rest. OA pain is caused by aberrant functioning of a pathologically altered nervous system with key mechanistic drivers from peripheral nerves and central pain pathways. This review focuses on symptomatic pain therapy exemplified by molecular targets that alter sensitization and hyperexcitability of the nervous system, for example, opioids and cannabinoids. We highlight opportunities for targeting inflammatory mediators and their key receptors (for example, prostanoids, kinins, cytokines and chemokines), ion channels (for example, NaV1.8, NaV1.7 and CaV2.2) and neurotrophins (for example, nerve growth factor), noting evidence that relates to their participation in OA etiology and treatment. Future neurological treatments of pain appear optimistic but will require the systematic evaluation of emerging opportunities.

Novel molecular targets in pain control.

PURPOSE OF REVIEW: The complexity of pain processing in clinical pain conditions and in animal models has revealed many time-related changes and an abundance of molecular drug targets. There continues to be insecurity, however, about new target validation in clinical pain and thus most analgesia development is of high risk for evolving new pain therapies. The present review highlights a number of molecular targets being pursued for pain control. RECENT FINDINGS: Many pain targets are critically dependent on the pain model/lesion type. Neural and glial plasticity, ranging from changes in molecular expression and receptor phosphorylation to profound morphological reorganization, has been described under these conditions. Pain modulation has been shown to involve all major families of regulatory proteins such as the G-protein coupled receptors, ion channels, regulatory enzymes, neurotrophins, and kinases, offering an abundance of targets and therapeutic opportunities for symptomatic pain relief. SUMMARY: Many molecular targets have been highlighted with some being the focus of current analgesia research. Some of these (e.g. vanilloid receptor 1, cannabinoid receptor 1, sodium channel NaV 1.8) have been evaluated in animal studies and in preliminary clinical studies, but others are highly novel and riskier analgesia pain targets (e.g. metabotropic glutamate receptors, sensory neurone specific receptors, kinase inhibitors).