疼痛与本体感受

In this chapter, you will learn about: ● Somatosensation and the primary sensory cortex. ● Nociception and the perception of pain. ● Common analgesics and local anaesthetics. Somatosensation and the sensory cortex Sensation Sensation is a remarkably important part of life. Patients who have lost sensation in some way end up unable to perform simple tasks such as undoing buttons and manipulating coins. In severe forms of sensory disturbance (such as the neuropathy that occurs with diabetes), patients may sustain severe injuries—particularly to the feet in diabetics—partly because they cannot feel the pain. There are four sensory modalities—touch, thermal sensation, pain and proprioception. In this chapter, we will not look at proprioception, which is covered in Chapter 5. There are individual receptors for submodalities within these groups. For example, the body can differentiate between light touch and pressure, between hot and cold and between mechanical and thermal pains. In humans, no matter how a receptor is activated (electrically or electromagnetically), the subjective sensation reported is always that of its modality. This has proved particularly useful for physiologists studying the processes! They have shown that there are modality-specific channels that convey information of one modality from the skin to the sensory receiving area. Receptors Receptors are formed by the peripheral terminations of the axons of dorsal root ganglion cells. Receptors in the skin may be free nerve endings, or associated with different connective-tissue structures (e.g. Pacinian corpuscles). Receptors can be divided into slowly adapting and rapidly adapting types. These two categories work in harmony to send different information about the same stimulus. The different signalling depends either on the linkage of the receptor to its incident energy or on a property called adaptation (i.e. a decline in receptor responsiveness even though the stimulus is still present). As a general rule, slowly adapting receptors signal the magnitude or location of a stimulus, whereas rapidly adapting receptors signal its rate of change and duration. The receptor membrane depolarizes in response to its modality stimulus, causing a generator potential. If sufficient, this causes the axon to depolarize to its threshold level and produce an action potential. Because the axon recovers after its refractory period, a long-lasting generator potential will cause the axon to fire a train of impulses whose frequency will be proportional to the magnitude of the generator potential. To accommodate the wide range of sensory experience, different unimodal receptors have different thresholds, and the generator potential has a logarithmic relationship between stimulus intensity, frequency of firing and ultimately perceived sensation. Fig. 4.1 shows different fibre types for different modalities and their conduction speeds and axonal diameters. The axons of these receptors enter the spinal cord via the dorsal root ganglion, with the fibres signalling modalities of touch travelling in the dorsal column pathway, and the fibres signalling thermal and pain information travelling in the spinothalamic tract (along with some information about crude touch). The dorsal column pathway and spinothalamic tract are discussed in detail in Chapter 3. The site of the sensory cortex and its organization are shown in Fig. 4.2. The homunculus is distorted because more of the cortex is used to process information from body areas used for exploration. Areas of greatest organized receptor density (i.e. other than free nerve endings) have the biggest representation in the sensory cortex. The sensory cortex has an homunculus for each modality (i.e. there is a map for touch, another for pressure, etc., all lying next to each other). Within each homunculus, there is a columnar organization from the cortical surface to the corpus callosum. Within each column, the cells have similar receptive fields and modality. The layers in the column send 47 4. Somatosensation and the Perception of Pain M3290-04.qxd 12/5/03 12:01 pm Page 47 The Somatosensory System 48 and receive fibres from different areas of the cortex and thalamus. This is shown in Fig. 4.3. Nociception Nociception is the sensory process detecting overt or impending tissue damage. Pain is the perception of irritating, sore, stinging, throbbing or painful Pattern of termination in Rexed’s laminae Sensory afferent fibres Modality proprioceptors from muscles, tendons mechanoreceptors from skin nociceptor, cold thermoreceptor nociceptor, heat thermoreceptor Axonal diameter (µm) Conduction speed (m/s) Class myelinated Aα Aβ Aδ unmyelinated C 20 10 2.5 <1 120 60 15 <1 III, IV, V III, IV, V I, II, V I, II Fig. 4.1 Sensory afferent fibres. thigh knee foot genitals neck upper limbfingers face teeth tongue pharynx central sulcus postcentral gyrus temporal lobe 1� sensory cortex Fig. 4.2 Homuncular organization and location of primary sensory cortex (S1). digit 2 digit 1 I II III IV V VI RA SA RA SA to ipsilateral sensory cortex, contralateral sensory cortex, parietal cortex, motor cortex from thalamus to basal ganglia, brainstem, cord to thalamus digit 2 Fig. 4.3 Columnar organization of primary sensory cortex (RA, rapidly adapting; SA, slowly adapting). M3290-04.qxd 12/5/03 12:01 pm Page 48 Somatosensation and the sensory cortex 49 sensations arising from the body. The way the body perceives pain not only depends on nociceptor input, but also on other pathways giving information about, for example, emotional components. Thus, pain is an ‘experience’ rather than a simple sensation. Although nociceptors do not show adaptation (i.e. they fire continuously to tissue damage), pain sensation may come and go and pain may be felt in the absence of nociceptor discharge. They rely on chemical mediators around the nerve ending which indicate tissue damage. Pain is somehow related to itch. Itch is also mediated by Aδ and C fibres; people born without a sense of pain show no sense of itch, but itch is unaltered by opiate drugs. Hyperalgesia is the phenomenon of increased sensitivity of damaged areas to painful stimuli: ● Primary hyperalgesia occurs within the damaged area. ● Secondary hyperalgesia occurs in undamaged tissues surrounding this area. After damage, blood vessels become leaky and the damaged tissue cells release a variety of chemicals that give a local response—inflammation (e.g. histamine, which directly excites nociceptors, and prostaglandin, which sensitizes nociceptors). Nociceptor afferent nerves release not only the excitatory transmitter glutamate (as do all sensory afferent nerves), but also the cotransmitter substance-P. This causes a very long-lasting excitatory postsynaptic potential and helps sustain the effect of noxious stimuli. Processing of nociceptive afferent nerves begins in the circuits in the dorsal horn and a certain amount of descending control is exercised over the firing of spinothalamic cells in lamina I. Pain information is then transmitted to the cortex in the spinothalamic tract (see Chapter 3). Whether the cortex is the ultimate site of pain sensation is a matter for debate. Certainly, subjects who are awake during neurosurgery do not report pain sensations when electrodes are passed through areas of the cortex. When those areas are stimulated, subjects may report tingling or thermal sensation, but not pain. It is likely then that the conscious sensation of pain has a large subcortical component. Referred pain Pain from internal organs (viscera) is felt as pain in a more superficial region of the body. Nociceptor fibres from viscera and from cutaneous structures converge on the same pain pathway (i.e. spinothalamic cells). The central nervous system can make no distinction between superficial pain and deep pain and consequently interprets all pain as superficial. For example: ● Pain of myocardial infarction is classically felt centrally just behind the sternum, radiating down the left arm and up the root of the neck into the jaw. ● Inflammation affecting the diaphragm is felt in the tip of the shoulder (phrenic nerve root values C3–C5). Regulation of pain Peripheral regulation Pain can be regulated by sensory input—it can be reduced by activity in low-threshold mechanoreceptors as their afferent nerves inhibit spinothalamic cell discharge, the phenomenon of ‘mummy rubbing it better’. Central regulation Pain can sometimes be suppressed by ‘willing it to go away’. A possible reason for this is that there are regions in the central nervous system that have been implicated in pain suppression (Fig. 4.4). Electrical stimulation of the periaqueductal grey matter in the midbrain causes profound analgesia. This area receives information from higher structures processing emotional states and projects to the midline reticular and raphe nuclei, which in turn project to the dorsal horns. Two other parts of the reticular formation—the nucleus reticularis paragigantocellularis and the locus coeruleus—are also implicated in modulating nociceptive neuronal activity in the dorsal horns. Opiates are thought to produce their antinociceptive action by activating these central regulating structures. Transcutaneous electrical nerve stimulation (TENS) can be used to activate large-diameter fibres to decrease the sensation of pain. This is particularly useful in chronic pain states (e.g. lower back pain) and increasingly is being used as non-invasive pain relief for women in labour. M3290-04.qxd 12/5/03 12:01 pm Page 49 Some of these regions contain endogenous opioid peptides, although pain modulation also involves 5-hydroxytryptamine (5-HT) from the raphe nuclei and noradrenaline from the locus coeruleus. There are three classes of endogenous peptides (shown in Fig. 4.5). There are three major classes of opioid receptor: ● µ (mu) ● δ (delta) ● κ (kappa) Morphine is a potent µ agonist and naloxone an antagonist. Endogenous enkephalins are active at both µ and δ receptors. Both receptor types are found in the periaqueductal grey matter and in laminae I and II of the dorsal horn. Note that each of these receptors is found throughout the central nervous system, suggesting that they are involved in processes other than pain perception. This explains the other effects of opiates, such as euphoria and hallucinations. Analgesia Analgesia is relief from the psychological state of pain, whereas antinociception is simply the blockage of nociceptive inputs. The main analgesics in clinical use are: ● Opioid analgesics acting on the endogenous system of pain control. ● Non-steroidal anti-inflammatory drugs, which reduce the production of inflammatory mediators that sensitize nociceptors to bradykinin and 5-HT. ● Simple analgesics (e.g. paracetamol). ● Local anaesthetics, which block action potential conduction along axons. ● Miscellaneous drugs (e.g. sumatriptan, a 5-HT1D agonist) in migraine; carbamazepine (antiepileptic) in trigeminal neuralgia; tricyclic antidepressants (amitryptyline) in some types of chronic pain. Opioids Opioid drugs bind to the receptors of the endogenous opioid transmitters. There are two classes of opioids: ● Opiates, which include morphine and analogues that are structurally similar to morphine and usually synthesized from it (e.g. diamorphine, codeine). ● Synthetic derivatives structurally unrelated to morphine (e.g. pethidine, fentanyl). Opioids block pain information from being transmitted up the spinothalamic tract (antinociceptive action) but they also act in the brain to reduce the unpleasantness of the pain state (analgesic action). The Somatosensory System 50 cortexhypothalamus thalamus periaqueductal grey matter (around aqueduct in midbrain) nucleus reticularis paragigantocellularis (NRPG) + + − + + spinal cord + pain dorsal horn nucleus raphe magnus (NRM) 5-HT enkephalin locus coeruleus noradrenaline reticular formation − − − Fig. 4.4 Central regulation of pain. M3290-04.qxd 12/5/03 12:01 pm Page 50 Somatosensation and the sensory cortex 51 ● The weaker opioids (such as codeine) are widely used in over-the-counter pain preparations, and often in conjunction with a simple analgesic in presciption medications (e.g. co-codamol is codeine and paracetamol). ● Stronger opioids (such as morphine and pethidine) are used in post-operative pain and sometimes in severe chronic pain (such as cancer pain). ● Either fentanyl or morphine are commonly used as part of general anaesthesia. The main effect of opioids is on the µ receptor, causing: ● Analgesia and antinociception. ● Euphoria and drowsiness—depending on the circumstances of administration. ● Respiratory depression—reducing the sensitivity of the brainstem to PaCO2. ● Miosis—pupillary constriction caused by stimulation of parasympathetic component of cranial nerve III. ● Nausea—stimulation of the chemoreceptor trigger zone in the brainstem which sends signals to the vomiting centre. ● Constipation—increased tone and reduced motility of gastrointestinal tract. There are problems with repeated administration of opioids: ● Tolerance—a gradual reduction in effect over repeated administration of the same amount of drug. Doses of morphine therefore need to be increased over time to produce the same degree of pain relief, but this causes a greater degree of constipation. ● Dependence—this can be physical (where a withdrawal syndrome of physical symptoms and signs like influenza occurs when the drug is not administered) or psychological (where compulsive drug-seeking behaviour develops). Often, it is a combination of both. The most common drug of abuse in this class is diamorphine (otherwise known as heroin), but it should be remembered that many patients will be taking opioids which are legitimately prescribed and will develop these side effects and may be at risk from overdose. The main danger of opioid abuse is from overdose, which presents with: ● Coma. ● Respiratory depression. ● Pin-point pupils (there is no tolerance to pupillary constriction even in the hardened addict). Treatment is with intravenous µ-antagonists, such as naloxone (rapidly acting and short duration of action) or naltrexone (longer to act but longer duration of action). Note that antagonists may stimulate an acute withdrawal state and supportive therapy alone (e.g. ventilation) may be appropriate in some cases of opioid overdose. The main opioids are shown in Fig. 4.6 with their different pharmacological properties and clinical uses. The opiate class of opioids (morphine, diamorphine, codeine) also inhibit histamine release from mast cells and are cough suppressants, but these effects are not mediated by opioid receptors. This is exploited by codeine-based cough linctuses. Location spinal cord, brainstem spinal cord, brainstem hypothalamus Opioid peptides Parent peptide proenkephalin prodynorphin pro-opiomelanocortin Opioid peptide enkephalins dynorphins β endorphin Amino acid sequence Leu5, Met5, and longer sequences all contain Leu5 within longer sequences Met5 in 31 amino acid sequence Fig. 4.5 Opioid peptides. M3290-04.qxd 12/5/03 12:01 pm Page 51 Non-steroidal anti-inflammatory drugs Non-steroidal anti-inflammatory drugs relieve pain by reducing the sensitization of nociceptors that occurs in inflammation. NSAIDs are also anti- inflammatory and antipyretic (decrease fever). They inhibit: ● Cyclooxygenase (which metabolizes arachidonic acid to prostaglandins). ● Leukotrienes (which have roles in continuing the process of inflammation). The prostaglandins, PGE1 and PGE2, lower the threshold of polymodal nociceptors to stimulation by the inflammatory mediators bradykinin and 5-HT. The production of prostaglandins in these normal circumstances is by a subtype of cyclooxygenase, cyclooxygenase-1. The other type, cyclooxygenase-2 (COX-2), is inducible and metabolizes arachidonic acid in inflammatory cells. Side effects of these drugs can result from interference with the physiological role of prostaglandins in the regulation of blood flow. For example, interfering with blood flow in the gastric mucosa reduces HCO3 – production. Gastric acid can then attack the mucosal surface causing ulceration and potentially fatal bleeding. This has lead to the introduction of selective COX-2 inhibitors which are marketed as being less damaging to the gastric mucosa (recent BMJ articles may not be protective!). Fig. 4.7 shows the main NSAIDs in clinical use with their effects and side effects. Fig. 4.8 shows the site of action of NSAIDs. Generally, NSAIDs are considered to be very safe drugs and are widely available. However, aspirin use has been linked to Reye’s syndrome in children (causing liver damage and encephalopathy after a The Somatosensory System 52 Bioavailability and administraion Poor availability when given orally due to high rate of first-pass metabolism. Intravenous administration gives reliable dosing More lipid soluble. Given orally or by intramuscular, intravenous or subcutaneous injection High oral bioavailability High lipid solubility. Given orally and by intramuscular injection High lipid solubility. Given intravenously, epidurally, transdermally Increased first-pass metabolism. Given sublingually, intra-thecally Given orally or by injection Metabolism active metabolite morphine-6-glucuronide partly to morphine to other opioids including morphine metabolite norpethidine interacts with MAOIs Potency and length of action t1/2 3 h very potent, rapid onset, t1/2 2 hrs one-sixth potency of morphine one-tenth potency of morphine very potent, short acting t1/2 12 h, slow onset t1/2 >24 h, very slow onset Notes cannot be given in labour as fetal liver cannot conjugate potent antitussive, low side effect profile does not cause miosis intra-operative analgesia partial agonist and difficult to reverse effects in overdose does not produce euphoria Clinical use acute and chronic pain acute and chronic pain mild pain, headache, dental pain acute pain, labour intra-operative pain acute and chronic pain maintenance of drug addicts Opioid drugs µ Agonist morphine diamorphine (heroin) codeine pethidine fentanyl buprenorphine methadone Fig. 4.6 Opioid drugs and their pharmacology (MAOI, monoamine oxidase inhibitors—a type of antidepressant). Naloxone is widely used in an emergency setting to treat acute overdose, but its duration of action is much shorter than most opioids which are abused. Therefore, it is important to carry on monitoring the patient to look for signs of relapse. M3290-04.qxd 12/5/03 12:01 pm Page 52 viral illness). Chronic NSAID use may also cause an interstitial nephritis, with lasting kidney damage in some patients. Local anaesthetic agents Local anaesthetic agents block the ability of axons to conduct action potentials by blocking Na+ channels in the axonal membrane. The blocking site on the Na+ channel is on its intracellular portion. Local anaesthetics are weak bases that can exist, depending on their pKa (the dissociation constant, calculated by the Henderson–Hasselbach equation), in either a hydrophilic state, when bound to H+, or in hydrophobic state without H+. ● In the hydrophobic state, they can pass straight through the lipid membrane to gain access to the blocking site, whether the channel is closed or open. ● In the hydrophilic state, they can enter only through the open mouth of the Na+ channel, and therefore need to wait until the channel opens to gain access to the blocking site. The hydrophilic route of the drug leads to ‘use-dependent’ block—the block of channels increases as more