Current Neuropharmacology - Volume 4, Issue 3, 2006

Although morphine is still the gold-standard for the treatment of pathological pain, the increasing knowledge of the mechanisms that regulate pain threshold breaks the ground for the development of new potent and safe analgesic drugs. Hopefully, these drugs will relieve some forms of pain that are partially resistant to opiates, such as neuropathic pain. This issue of Current Neuropharmacology includes a series of excellent reviews that summarize the current knowledge and the most exciting perspectives on the neurobiology of pain. The opening review by Dr. Marchettini and collaborators is a nice clinical classification of peripheral neuropathies, which are a major source of neuropathic pain. If present, pain associated with peripheral neuropathies is extremely disabling, and its treatment is one of the major challenges in neuroscience. The two following reviews by Dr. Story and Dr. Mc Naughton’s group focus on the role of Trp channels in heat sensation and inflammatory pain. One of these channels, named TrpV1, is expressed by neurons of dorsal root ganglia, and responds to heat, protons, inflammatory mediators, and capsaicin. An increased sensitivity of the TrpV1 channel is central to the pathophysiology of heat hyperalgesia in inflammatory pain. The review by the group of Dr. Negri and Dr. Melchiorri describes the role of prokineticins and their receptors in the modulation of pain. Prokineticins are the mammalian homologs of Bv8, a small protein extracted from the frog skin that behaves as a potent hyperalgesic agent. The regulation of pain moves from the periphery to the CNS in the review by Dr. Tao and Dr. Johns, which describes the role of PDZ-domain-containing proteins associated with NMDA receptors in persistent pain. The review by the group of Dr. Maione and Dr. Rossi explores the complex interaction between metabotropic glutamate receptors and cannabinoid receptors in the periaqueductal grey, a region of the brainstem that is critical for the regulation of pain threshold. These two classes of receptors are considered as potential targets for novel analgesic drugs. Along this line, the review by Dr. Chiechio and collaborators describes the mechanism of action of Lacetylcarnitine, a drug that is currently used for the treatment of neuropathic pain. L-Acetylcarnitine up-regulates the expression of a particular metabotropic glutamate receptor subtype, the mGlu2 receptor, which inhibits neurotransmission at the synapse between primary afferent pathways and neurons in the dorsal horns of the spinal cord. Finally, the elegant review by Dr. Manzanares, Dr. Julian, and Dr. Carrascosa describes the multifaceted role of the cannabinoid system in pain transmission, and the potential therapeutic implications for the management of acute and chronic pain. Taken together, the articles included in the issue offer an original view of the molecular and transsynaptic mechanisms underlying inflammatory and neuropathic pain, and are particularly helpful for basic scientists and clinicians interested in the neuropharmacology of pain.

Peripheral neuropathies are a heterogeneous group of diseases affecting peripheral nerves. The causes are multiple: hereditary, metabolic, infectious, inflammatory, toxic, traumatic. The temporal profile includes acute, subacute and chronic conditions. The majority of peripheral neuropathies cause mainly muscle weakness and sensory loss, positive sensory symptoms and sometimes pain. When pain is present, however, it is usually extremely intense and among the most disabling symptoms for the patients. In addition, the neurological origin of the pain is often missed and patients receive inadequate or delayed specific treatment. Independently of the disease causing the peripheral nerve injury, pain originating from axonal pathology or ganglionopathy privileges neuropathies affecting smaller fibres, a clinical observation that points towards abnormal activity within nociceptive afferents as a main generator of pain. Natural activation of blood vessels or perineurial nociceptive network by pathology also causes intense pain. Pain of this kind, i.e. nerve trunk pain, is among the heralding symptoms of inflammatory or ischemic mononeuropathy and for its intensity represents itself a medical emergency. Neuropathic pain quality rekindles the psychophysical experience of peripheral nerves intraneural microstimulation i.e. a combination of large and small fibres sensation temporally distorted compared to physiological perception evoked by natural stimuli. Pins and needles, burning, cramping mixed with numbness, and tingling are the wording most used by patients. Nociceptive pain instead is most often described as aching, deep and dull. Good command of peripheral nerve anatomy and pathophysiology allows timely recognition of the different pain components and targeted treatment, selected according to intensity, type and temporal profile of the pain.

Pain is universal and vital to survival. It is an essential component of our sense of touch; together, touch and pain have evolved to enable our awareness of the intricacies of our environment and to warn us of danger and possible injury. There is a clear link between temperature sensation and pain-painful temperature sensations occur acutely and are a hallmark of inflammatory and chronic pain disorders of the nervous system. Mounting evidence suggests a subset of Transient Receptor Potential (TRP) ion channels activated by temperature (thermoTRPs) are important molecular players in acute, inflammatory and chronic pain states. Varying degrees of heat activate four of these channels (TRPV1-4), while cooling temperatures ranging from pleasant to painful activate two distantly related thermoTRP channels (TRPM8 and TRPA1). ThermoTRP channels are also chemosensitive, being activated and or modulated by plant-derived small molecules and endogenous inflammatory mediators. All thermoTRPs are expressed in tissues essential to cutaneous thermal and pain sensation. This review examines the contribution of thermoTRP channels to our understanding of temperature and pain transduction at the molecular level.

Injury or inflammation release a range of inflammatory mediators that increase the sensitivity of sensory neurons to noxious thermal or mechanical stimuli. The heat- and capsaicin-gated channel TRPV1, which is an important detector of multiple noxious stimuli, plays a critical role in the development of thermal hyperalgesia induced by a wide range of inflammatory mediators. We review here recent findings on the molecular mechanisms of sensitisation of TRPV1 by inflammatory mediators, including bradykinin, ATP, NGF and prostaglandins. We describe the signalling pathways believed to be involved in the potentiation of TRPV1, and our current understanding of how inflammatory mediators couple to these pathways.

Bv8 is a small protein secreted by frog skin. Mammalian homologues of Bv8, the prokineticins PK1 and PK2, and their G-protein coupled receptors PKR1 and PKR2 have been identified and linked to several biological effects. Bv8 elicits a dose-dependent reduction in nociceptive threshold to thermal and mechanical stimuli applied to the skin of tail and paw of rats and mice and increases the sensitivity to nociceptive mediators as capsaicin and prostaglandins. The receptors for Bv8/PKs are present in a fraction of peptidergic population of C-fibre neurons, and in a fraction of A myelinated- fibre neurons. In mouse and rat dorsal root ganglia, PKR-expressing neurons also express TRPV1 and the activation of PKRs sensitises TPRV1 to the action of capsaicin. Mice lacking PKR1 gene exhibit impaired Bv8-induced hyperalgesia, develop deficient responses to noxious heat, capsaicin and protons and show reduced thermal and mechanical hypersensitivity to paw inflammation, indicating a requirement for PKR1 signalling associated with activation and sensitisation of primary afferent fibres. PKs are highly expressed by neutrophils and other inflammatory cells and must be considered as new pronociceptive mediators in inflammatory tissues. Bv8-like hyperalgesic activity was demonstrated in extracts of rat inflammatory granulocytes. Bv8 stimulate macrophage and T lymphocyte to differentiate between an inflammatory and Th1 profile indicating that Bv8/PK proteins play a role in immuno-inflammatory responses. Blockade of PKRs may represent a novel therapeutic strategy in acute and inflammatory pain conditions.

Persistent pain, a common clinical condition, could be caused by inflammation, tissue injury secondary to trauma or surgery, and nerve injuries. It is often inadequately controlled by current treatments, such as opioids and nonsteroidal anti-inflammatory drugs. The PDZ (Postsynaptic density 95, Discs large, and Zonula occludens-1) domains are ubiquitous protein interaction modules often found among multi-protein signaling complexes at neuronal synapses. Recent preclinical research shows that targeted disruption of PDZ domain-mediated protein interaction among N-methyl-Daspartate (NMDA) receptor signaling complexes significantly attenuates the development and maintenance of persistent pain without affecting nociceptive responsiveness to acute pain. PDZ domains at excitatory synapses may be new molecular targets for prevention and treatment of persistent pain. Here, we illustrate expression and distribution of the PDZ domain- containing proteins associated with NMDA receptors in the pain-related regions of the central nervous system, review the evidence for their roles in persistent pain states, and discuss potential mechanisms by which these PDZ domaincontaining proteins are involved in persistent pain.

Metabotropic glutamate (mGlu) and cannabinoid receptors are G-protein coupled receptors which have shown synaptic co-operation through small lipid messengers in the central nervous system (CNS). A functional interaction between these two receptor families could have a relevant potential in the treatment of CNS disorders, including chronic pain. Indeed, both mGlu and cannabinoid receptors play a crucial role in the neurobiology of pain and their simultaneous manipulation could lead to novel strategies in pain management. In particular, as both mGlu and cannabinoid receptors have been found in the periaqueductal gray (PAG), a crucial station in the pain modulatory system, these receptors could be a substrate for producing analgesia at this level. In this review we aim to briefly illustrate the role of mGlu and cannabinoid receptors in controlling nociceptive processes, some points of convergence, and their functional interaction in pain processing. Further insights into this functional linkage between the mGlu and cannabinoid receptors could pave the way to a new strategy for pain relief, such as a drug cocktail acting on cannabinoid/metabotropic glutamate receptors.

During the past two decades, many pharmacological strategies have been investigated for the management of painful neuropathies. However, neuropathic pain still remains a clinical challenge. A combination of therapies is often required, but unfortunately in most cases adequate pain relief is not achieved. Recently, attention has been focused on the physiological and pharmacological effects of L-acetylcarnitine in neurological disorders. There are a number of reports indicating that L-acetylcarnitine can be considered as a therapeutic agent in neuropathic disorders including painful peripheral neuropathies. In this review article, we will examine the antinociceptive and the neuroprotective effects of Lacetylcarnitine as tested in clinical studies and in animal models of nerve injury.

Cannabis extracts and synthetic cannabinoids are still widely considered illegal substances. Preclinical and clinical studies have suggested that they may result useful to treat diverse diseases, including those related with acute or chronic pain. The discovery of cannabinoid receptors, their endogenous ligands, and the machinery for the synthesis, transport, and degradation of these retrograde messengers, has equipped us with neurochemical tools for novel drug design. Agonist-activated cannabinoid receptors, modulate nociceptive thresholds, inhibit release of pro-inflammatory molecules, and display synergistic effects with other systems that influence analgesia, especially the endogenous opioid system. Cannabinoid receptor agonists have shown therapeutic value against inflammatory and neuropathic pains, conditions that are often refractory to therapy. Although the psychoactive effects of these substances have limited clinical progress to study cannabinoid actions in pain mechanisms, preclinical research is progressing rapidly. For example, CB1- mediated suppression of mast cell activation responses, CB2-mediated indirect stimulation of opioid receptors located in primary afferent pathways, and the discovery of inhibitors for either the transporters or the enzymes degrading endocannabinoids, are recent findings that suggest new therapeutic approaches to avoid central nervous system side effects. In this review, we will examine promising indications of cannabinoid receptor agonists to alleviate acute and chronic pain episodes. Recently, Cannabis sativa extracts, containing known doses of tetrahydrocannabinol and cannabidiol, have granted approval in Canada for the relief of neuropathic pain in multiple sclerosis. Further double-blind placebo-controlled clinical trials are needed to evaluate the potential therapeutic effectiveness of various cannabinoid agonists-based medications for controlling different types of pain.