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PAIN MECHANISMS - WHAT WE KNOW ABOUT HOW THEY WORK
University College, London, England
Pain, of all our senses, is unique in that the sensory aspects of the stimulus comes with unpleasant psychological effects. This is a system with enormous functional implications for human health and suffering. The suffering that pain brings can be immense and there are many pain syndromes, even in highly developed countries, that are poorly controlled by present medication. The prevalence of pain is underestimated and a recent WHO study reported that the prevalence of long term pain in 1998 was 22% in a survey of more than a dozen countries. The cost in terms of human suffering is immense yet the economic costs are also considerable. The price of low back pain is greater than coronary heart disease, stroke, depression and migraine and the incidence is similar to the figure above, between 12 - 35%.
Thus there is little doubt that new approaches to the control of pain are needed. However, if new pharmaceuticals are to be produced then we need to have a clear understanding of the neurobiology of pain, and especially the roles of pharmacological systems in the nervous system, important for the transmission of painful messages from their origins in the periphery to their final elaboration at the highest centres of the brain. The latter sites are the hardest to study so that most of what we know is from studies of the peripheral nerve and the spinal cord. Apart from the potential for the development of new targets and strategies for the treatment of clinical pain syndromes, the study of pain is a model for the investigation of how the nervous system deals with, and adapts to inputs from the outside world.
Plasticity is inherent in the sensory pathways in that the neuronal systems alter in different pain states. The aim of this overview is to summarize the potential targets at both peripheral and central levels for novel analgesic therapy. If and when drugs are produced with selective actions at these targets then clinical studies will be of the utmost importance in the determination of effectiveness and the relative balance between wanted and unwanted effects of these novel agents. What follows is a guide to the preclincial evidence for roles of receptors and channels in different pain states.
TYPES OF PAIN TRANSMISSION
In order to study the receptor systems involved in the transmission of pain and its modulation, there is a need for consideration of processes occurring at the peripheral endings of sensory neurones as well as events within the central nervous system. Whereas acute pain, short-lasting and self-limiting, rarely presents as a major clinical problem, pain caused by inflammation or tissue damage can be produced by surgical procedures, trauma, childbirth, cancer and disease states such as arthritis and rheumatism.
Inflammatoly pain is one of the major pain states. In addition, pain from nerve damage, neuropathic pain, can be produced by trauma, viral infections (post-herpetic neuralgia, AIDS), metabolic disorders (diabetes) and also tumours invading nervous tissue. Inflammation and neuropathy can obviously co- exist in a patient - post-surgical and traumatic pain states and also cancer pains are often mixed in terms of both tissue and nerve damage. The mechanisms of inflammatory and neuropathic pain are very different from acute pain and from each other and there is considerable plasticity in both the transmission and modulating systems in these prolonged pain states, plasticity that occurs at both peripheral and central sites.
In order to develop new strategies for the treatment of pain, models have to be developed that take into account these different mechanisms and the plasticity inherent in the pharmacology. The models have to mimic the clinical aspects of the condition and this approach has been successful, mainly as a result of interactions between basic scientists and clincians. The models of inflammation and neuropathy arecritical for better analgesics since acute pain does not involve many of the chemical ransmittersreceptors and channels important in the more persistent pain states. "These animal studies of inflammatory and neuropathic pain allow access to the peripheral endings of C-fibres, the spinal corditself and drugs can also be given systemically. The use of selective agonists and antagonists to the various receptor systems in different models allows plasticity to be monitored. Overall, the best tactic has been to attempt to show an alteration of a physiological response to a particular painful stimulus by a selective antagonist. This provides the best evidence for a role of that transmitter and receptor in a particular pain state.
The transmission of acute pain involves activation of sensory receptors on peripheral C-fibres, the nociceptors, which respond to noxious mechanical and thermal stimulation. However, once tissue damage and inflammation occurs, the production of chemical mediators in the damaged area of tissue becomes of great importance. Thus, prostanoids are produced from local cell membranes, bradykinin is liberated from its precursor in the vasculature and 5HT is also released. The actions of these mediators on their excitatory receptors located on the peripheral C-fibres plays a major role in the sensitisation and, at higher concentrations, the activation of C-fibres during inflammation. The former action, sensitization, arises from these mediators acting to reduce the threshold of the sensory nerves so that they now respond to lower intensity stimuli, the basis for the tenderness following injury to tissue. The original treatment for inflammation was aspirin which was known to be effective prior to the discovery of its mode of action. It is now very clear that the ability of the whole range of non-steroidal anti- inflammatory drugs (NSAIDs) to produce an analgesia in inflammatory pain states is based on their ability to block the production of the prostanoids. They do so by inhibition of the enzyme, cyclooxygenase that produces these mediators and so reduce sensitization and pain. The production of prostanoids in other parts of the body is, however, beneficial so that these drugs have a high liability for gastric side-effects. The concept of plasticity has been harnessed so that a second form of tfie enzyme, cyclooxygenase-2, induced at the site of tissue damage can now be inhibited. This strategy results is drugs with similar efficacy but lowered side-effects, an important advance. At present there are no drugs that target bradykinin and the triptans, drugs that act on the 5HT IB/D receptors, are exclusively for headache and not for pains in other areas of the body. Other factors such as induction of, and changes in agents such as Nerve Growth Factor and cytokines are also important at the peripheral level and resultant changes in the phenotype of the sensory neurones is likely to be important - at present we cannot target these agents but the principle of attemting to prevent maladaptive plasticity is important in all these examples.
Neuropathic pain syndromes are sensory disorders that arise from changes resulting from damage or dysfunction of neuronal pathways, peripheral or central. It is somewhat of a paradox that after damage to nerve and/or neurones, neuropathic pain is often characterized by both positive, (abnormal spontaneous or evoked sensations) and negative symptoms (sensory deficits) - intuitively only the latter might be expected. Not only can there be an ongoing pain in areas of sensory loss but a range of natural stimuli, when applied, may evoke painful or unpleasant sensations Early animal studies related to neuropathic pain used complete nerve section, ~ore recent animal models are based on a restricted partial denervation of the hindlimb following sciatic nerve injury. Two of the models involve constriction of the sciatic nerve distal to the spinal cord, either a tight ligation of a portion of the sciatic nerve ( partial ligation model,) or the loose ligation of the entire nerve (chronic constriction injury [CCI] model). The most recent model uses tight ligation of two of the three spinal nerves which form the sciatic nerve (spinal nerve ligation [SNL] model). The behavioural consequences of these models mimic some aspects of the human symptoms, although the extent and location of the injury differ between the various models.
There is evidence that the aberrations in somatosensory processing which follow partial nerve injury are the culmination of a number of changes in the peripheral nervous system. Studies after nerve section suggest that the generation of ectopic discharges within the neuroma and the dorsal root ganglia (DRG) contributes to these changes. After partial denervation (CCI model) high frequency spontaneous activity originating in the dorsal root ganglion targets the spinal neurones via injured A-fibres Both peripheral nerves and DRGs contribute to the behavioural responses including allodynia, associated with the SNL model. In this same model, a novel 'modified rapidly adapting' mechanoreceptor has been reported, suggesting changes in transduction processes and there are a number of neurochemical changes in the sensory nerves; some peptide transmitters are deleted whilst novel peptides are induced. A structural reorganisation of large fibre (Abeta) termination at the level of the spinal cord has also been reported so that it is possible that low threshold inputs can now gain access to spinal nociceptive transmission circuits. "Neuropathic pain states are therefore generated in the peripheral sensory neurones by events that are independent of nociceptors. Clustering of sodium channels around areas of nerve damage set up ectopic activity that can spread to the ganglion cells. Sympathetic activity can facilitate these events. Thus membrane stabilizers, drugs that block sodium channels, developed as anticonvulsants, and also agents acting on the sympathetic nervous system have taken their place in the control of neuropathic pain. The reasons why these agents work has only been evident quite recently. Can we improve upon these drugs? The answer is that there is considerable potential, based on the finding that C-fibres have unique sodium channels which differ from all other sodium channels in other nerves, neurones and those in the heart. These channels may become important targets for drugs. Recently, a number of Other channels and receptors which respond to heat, capsaicin; purines and protons (low pH) have been characterized in peripheral nerve and so may also turn out to be novel targets for peripherally acting analgesics.
CENTRAL EXCITATORY SYSTEMS
The arrival of sensory information from nociceptors in the dorsal horn of the spinal cord adds considerable complexity to the study of pain and analgesia. The density of neurones in these areas is equal to or exceeds that seen elsewhere in the CNS. Interactions between peptides and excitatory amino-acids (BAA) are critical for pain transmission from peripheral nerve to the spinal cord and then to the brain. The AMPA receptor for the EAA sets the baseline response of the spinal neurones and is active during both noxious and innocuous responses.
Kainate receptors on terminal and neurones may also be important in the generation of neuronal activity. Release of peptides and their receptor actions allows the NMDA receptor for glutamate to be activated. Activation of the NMDA receptor underlies wind-up, whereby the baseline response is amplified and prolonged even though the peripheral input remains the same. This increased responsivity of dorsal horn neurones is probably the basis for central hypersensitivy. The NMDA receptor is involved in persistent inflammatory and neuropathic pains where it is critical for both the induction and subsequent maintenance of the enhanced pain state. Antagonists at multiple sites on the NMDA receptor complex, including the licensed drug, ketamine, are effective in a number of animal models but also in humans. Both volunteer and clinical studies support the ideas that have come from basic research in that the NMDA receptor appears to underlie the central transmission of inflammatory post-operative and neuropathic pains. Novel NMDA receptor antagonists are eagerly awaited as the present drugs all have problematic side-effects. Calcium channels on terminals and neurones are important for both transmitter release and neuronal excitability. L, N and P-type calcium channel antagonists have distinct differential and time-dependent effects on acute, neuropathic and inflammatory nociception but are presently generally restricted to spinal routes of administration.Interestingly, gabapentin, an anticonvulsant that is also an analgesic, appears to produce its therapeutic effects by actions on calcium channels.
CENTRAL INHIBITORY SYSTEMS
Opium is one of the oldest drugs known to mankind. Morphine is still the gold standard for the control of moderate to severe pain and still now, most clinically used drugs act on the mu receptor for morphine. The roles of the mu, delta and kappa opioid receptors have been well established and the delta receptor may provide a target for opioids with less side-effects as compared with morphine.
Recently, a fourth receptor for opioids has been characterized. This newly discovered opioid receptor- like (ORL-I) receptor appears to be an inhibitory receptor despite the endogenous agonist having been named nociceptin (orphanin FQ). Overall, this peptide produces spinal analgesia but may well function as an "anti-opioid" at supraspinal sites.
The mu receptor is remarkably similar in structure and function in all species studied so that basic studies will be good predictors for human applications. The detailed structure of these receptors has been described and and we now have a reasonable understanding of their relative roles in physiological events. The best described central sites of action of morphine are at spinal and brain stem/midbrain loci. There will certainly be other actions at the highest centres of the brain but these are poorly understood. Opioids given systemically will act throughout the body.
The spinal actions of opioids and their mechanisms of analgesia involve 1) reduced transmitter release from nociceptive C-fibres so that spinal neurones are less excited by incoming painful messages, and 2) post-synaptic inhibitions of neurones conveying infromation from the spinal cord to the brain. This dual action of opioids can result in a total block of sensory inputs as they arrive in the spinal cord. However, a number of pathological factors can influence the degree of opioid analgesia and these are relevant to pain after nerve injury. One well established example is the reduction in spinal opioid receptor number seen after nerve section which may be an explanation of the poor opioid sensitivity of post-amputation pains. Less severe nerve damage can increase the levels of the non opioid peptide cholecystokinin (CCK), either spinally or supraspinally which acts as a negative influences on opioid actions. Antagonists at the CCKB receptor have predicted actions in enhancing or restoring morphine analgesia.
Adenosine appears to be released in response to NMDA receptor activation and then, by actions on the Al receptor, acts as a negative feedback system. Receptor agonists and agents that prevent the degradation of this purine are being developed.
The brain can talk to the spinal cord. Monoamine systems, originating in the midbrain and brainstem act to control the spinal transmission of pain. Alpha2 adrenoceptors appear to be important but most ofthe drugs in this class have marked sedative effects. There is still great confusion regarding the relative roles of the multiple 5HT receptors but drugs acting on this transmitter are highly effective in headache.
GENERAL COMMENTS AND PROVISOS
There are important differences in both .the response to a noxious stimulus and to the analgesic effects of morphine in different strains of mice. The extent of individual differences between patients is unknown but should be considered.
These are exciting times for pain control. Approaches ranging from molecular through to integrated systems are leading to the discovery of new targets - a rational basis for the development of new analgesics is being produced.
How does all this relate to fibromyalgias? There is good evidence that N-type and to a certain extent, P- type, calcium channels are more active after nerve or tissue injury - this will cause greater transmitter release mto' the spinal cord, itself driven by any peripheral pathology or malfunction. In turn, this increase transmitter actions will cause wind-up and central spinal hyperexcitability leading to an amplification and spread of the pain. Interestingly, a recent psychophysical study shows that patients with fibromyalgia have enhanced wind-up.
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3. Dray A, Urban L and Dickenson AH. (1994) Pharmacology of Chronic Pain. Trends in Pharm. ScL, 15: 190-7.
4. McMahon SB, Lewin GR, Wall PD. (1993) Central excitability triggered by noxious inputs. Current Opinion in Neurobiol. 3:602-610.
5. The Pain Series (1999) The Lancet 353.
6. Staud R, Vierck CJ, Cannon RL, Mauderii AP, Price DD. (2001) Abnormal sensitization and temporal summation of second pain (wind-up) in patients with fibromyalgia syndrome. Pain 91: 165-175.
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