Pain Management in Veterinary Practice

By Tom Doherty

Pain Management in Veterinary Practice provides veterinary practitioners with the information needed to recognize and manage pain in a wide range of large, small, and exotic animal species. Encompassing acute, adaptive, and chronic, maladaptive pain, the book provides an up-to-date review of the physiology and pathophysiology of pain. Pain Management in Veterinary Practice offers specific strategies for addressing pain in animals, including local and regional analgesia, continuous rate infusions, and novel methods of analgesic drug delivery.

With comprehensive information on the pharmacokinetic and pharmacodynamic characteristics of analgesic drugs, the book goes beyond pharmaceutical options to incorporate scientific information on techniques for complementary treatment, including physical therapy, acupuncture, chiropractic techniques, and nutritional strategies. Pain Management in Veterinary Practice is a valuable resource for developing pain management protocols in the veterinary clinic.

• Language: English
• Publisher: Wiley
• Release date: Oct 18, 2013
• ISBN: 9781118761601

Book preview

1

Introduction: Pain: An Issue of Animal Welfare

Alice Crook

There has been considerable progress since the early 1990s in pain research in animals and in our understanding of related physiology and pharmacology, enabling great strides to be made in pain management. But pain is still a huge welfare issue for animals: farm animals are routinely subjected to painful husbandry procedures with no anesthesia or analgesia; perioperative pain management in small and exotic animals is inconsistent; and management of cancer-related and chronic pain remains a challenge. Pain can diminish animal well-being substantially due to its aversive nature, the distress arising from the inability to avoid such sensations, and the secondary effects that may adversely affect the animal's quality of life (QOL). Pain may affect an animal's appetite, sleep habits (e.g., fatigue), grooming (e.g., self-mutilation), ability to experience normal pleasures (e.g., reduced play and social interaction), personality and temperament, and intestinal function (e.g., constipation), and may prolong the time needed for recovery from the underlying condition (ACVA, 1998; McMillan, 2003). Untreated pain may also result in systemic problems; for example, hepatic lipidosis in cats as a result of inappetance and inadequate caloric intake (Mathews, 2000).

Much is known about the recognition and assessment of pain in animals; however, more work is needed to develop valid and reliable pain scoring systems for all species that are practical in real-life situations. Perception of animal pain directly affects analgesic usage, and there is a wide range in attitudes among veterinarians, farmers, and pet owners. This can best be addressed through education. There are also economic, regulatory, and other constraints to effective pain management, particularly in large animals.

RECOGNITION AND ASSESSMENT OF PAIN IN ANIMALS

Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage (IASP, 1994). The experience of pain is always subjective. Self-reporting is the gold standard in people, yet how can we know the experience of animals?

Three approaches are used in the recognition and measurement of pain in animals. The first approach includes measures of general body function or productivity (e.g., food and water intake, weight gain) that are relatively easy to quantify; such measures reflect what was happening to the animal over the period between observations. The second approach includes physiological measures (such as changes in heart rate or cortisol concentrations) that are widely used in studies assessing pain in animals (Stafford & Mellor, 2005; Vickers et al., 2005; Whay et al., 2005) and are, in principle, particularly useful in prey species that are considered stoic and therefore unlikely to show pronounced behavioral responses until injuries are advanced (Phillips, 2002; Rutherford, 2002). However, the physical restraint required to obtain such measurements may itself be stressful and confound the results (Weary et al., 2006). Also, while cortisol measurements are useful for comparing treatments and controls, they are not useful in assessing the degree of pain an individual animal is experiencing (Rutherford, 2002).

Behavioral measures—the third approach—represent a way in which animals can self-report. Weary (2006) provides a comprehensive review of the ways such measures are used to recognize and quantify animal pain, and discusses the evidence necessary to ensure that the measures are valid (i.e., that the measure provides useful information about the pain the animal is experiencing) and reliable (i.e., repeatable). The three main classes of behavior used in pain assessment are pain-specific behaviors (e.g., gait impairment in lame dairy cows (Flower et al., 2008) or head shaking and rubbing in dehorned dairy calves (Vickers et al., 2005)); a decline in frequency or magnitude of certain behaviors (e.g., locomotory behaviors in rats postoperatively) (Roughan & Flecknell, 2003); and choice or preference testing (e.g., hens' responses to different concentrations of carbon dioxide used in stunning) (Webster & Fletcher, 2004). Rutherford (2002) discusses the usefulness of behaviors associated with acute, subacute, and longer-lasting pain in assessing the experience of pain in animals, including specific parameters that may be useful for veterinarians in clinical assessment of pain and by scientists studying pain in animals. These include simple and more complex behavioral responses, both qualitative and quantitative, which may or may not be adaptive, such as behaviors associated with escape or avoidance, guarding or protection (e.g., postural changes), and depression or learned helplessness.

Pain Recognition Tools

Pain researchers and clinicians alike agree that there is a need for sensitive and specific measures that are practical for real-time assessments in a variety of animal settings including farms, veterinary clinics, and laboratories (Viñuela-Fernández et al., 2007). Multidimensional pain scales that integrate objective and subjective behavioral observations with various other measures can be used to characterize an individual animal's experience of pain (Rutherford, 2002). Another approach is to develop questionnaires for use by animal owners that can be used in the assessment of pain and its impact on QOL (McMillan, 2003; Wiseman-Orr et al., 2004; Yazbek & Fantoni, 2005). Wiseman-Orr (2006) provides a thorough discussion of the approaches and potential pitfalls of designing and validating questionnaires where self-reporting is not possible and the questionnaires are designed for use by a proxy, as in the case of animals. Work continues in the development of scientifically validated pain recognition tools for veterinarians for clinical assessment of pain and for scientists studying pain in large, small, exotic, and laboratory animals (Roughan & Flecknell, 2003; Wiseman-Orr et al., 2004; Yazbek & Fantoni, 2005; Morton, 2005; Wojciechowska et al., 2005; Föllmi et al., 2007; Flecknell et al, 2007; Weary & Fraser, 2008).

PAIN AND CONSCIOUSNESS

Pain is always subjective and psychological variables such as past experience, attention, and other cognitive activities affect the individual's experience of pain (Melzack, 1993). Self-reporting is the gold standard in people and, because of the subtlety of communication possible with language, the understanding of pain has been greatly advanced through human subjects' descriptions of pain and the effects of different modalities of analgesia (Johnson, 2008). However, The inability to communicate verbally does not negate the possibility that an individual is experiencing pain and is in need of appropriate pain-relieving treatment (IASP, 1994).

If we cannot know the subjective emotional experiences of other human beings, how can we possibly know the emotional experience of animals? For most people, the evidence that animals have nociceptive receptors and pathways, physiological responses, and behavioral reactions to pain similar to that of people, is sufficient to accept that animals experience pain and suffer as a result. However, some scientists, surprisingly, suggest that animals are not capable of experiencing pain. Psychologist Bermond (2001), for example argues that animals other than anthropoid apes have an irreflexive consciousness (a consciousness without past or future) due to the lack of a well-developed prefrontal cortex, and that reflection is a requirement to experience suffering and pain as unpleasant. Therefore, he distinguishes between the registration of pain as a stimulus, which does not induce feelings of suffering and the experience of pain as an emotion, which does induce suffering (Bermond, 2001).

What kind of observations can provide evidence for or against the experience of pain and other affective states in animals? The neurophysiologist Gentle (2001) carried out an elegant series of studies to provide information on cognitive perception of pain in chickens by looking at the effect of selective attention on pain-related behavior. Noting that the human experience of pain can be modulated by shifts in attention through such modalities as relaxation training, hypnosis, and other therapies, he reasoned that if a chicken's response to a painful event was simply an unconscious automatic reaction the response would not be influenced by shifting the bird's attention. On the other hand, if the bird actually felt the pain as an unpleasant experience, redirecting its attention might reduce the signs of pain, as in people (e.g., installation of overhead television screens in dental offices). In his work, Gentle induced gout in one leg of chickens by injecting sodium urate crystals. Chickens kept in barren cages avoided placing weight on the affected leg and, if encouraged to walk, did so with a limp. These pain-related behavioral signs were greatly reduced or eliminated in chickens given a variety of motivational changes including nesting, feeding, exploration, and social interaction. The shifts in attention not only reduced pain but also reduced peripheral inflammation.

This work has far-reaching consequences. The evidence that motivational changes, by altering the birds' attention, significantly altered pain-related behaviors, and hence probably the pain experience for the animal, indicates a cognitive component of pain in the chicken and provides evidence of consciousness. On a practical level, these results also reinforce the importance of environmental enrichment, which will promote shifts in attention and, thereby, potentially improve the welfare of birds suffering pain under commercial conditions. Strategies, such as distraction and refocusing attention through positive interaction, are very familiar to veterinarians and animal health technicians as adjuncts to pain management in small animals in clinical settings.

ATTITUDES TOWARD ANIMAL PAIN

Freedom from pain, injury, or disease (by prevention or rapid diagnosis and treatment) is one of the Five Freedoms widely accepted as the major components of good animal welfare (Farm Animal Welfare Council, 2009). The recognition and effective treatment of pain is central to animal welfare (Rutherford, 2002). There is a strong emphasis on pain among animal welfare researchers, with the number of pain-related articles in scientific journals considerably outweighing articles on the other Freedoms (freedom to behave normally, freedom from fear and distress, freedom from hunger and thirst, and freedom from discomfort) (Phillips, 2008).

National animal welfare advisory bodies in Australia, New Zealand, and the European Union have recommended steps to avoid or minimize animal pain and associated suffering, and the World Organization for Animal Health (OIE) produced a special edition in its Technical Series on Scientific assessment and management of animal pain (Mellor et al., 2008). Veterinary associations commonly have positions or policies advocating the effective management of pain in animals (CVMA, 2007; AVMA, 2011).

In theory, then, we agree that animals should not be in pain, yet studies show that attitudes toward pain vary greatly among societal groups responsible for animal care, including veterinarians. Veterinary attitudes toward pain and pain management in companion and production animals have been studied in Canada (Dohoo & Dohoo, 1996; Hewson et al., 2006b, 2007a, 2007b), the United States (Hellyer et al., 1999), the United Kingdom (Lascelles et al., 1999; Capner et al., 1999; Huxley, 2006), Finland (Raekallio et al., 2003), Scandinavia (Thomsen et al., 2010), Europe (Hugonnard et al., 2004; Guatteo et al., 2008), and New Zealand (Laven et al., 2009). Other surveys have looked at the attitudes of veterinary and animal science students (Levine et al., 2005; Heleski & Zanella, 2006; Kielland et al., 2009).

These studies reveal some common themes. Considerable variation in clinical recognition and treatment of pain exists in both companion and production animal practice. A perception that an animal is in pain is a decisive factor in the provision of analgesia, yet there is great variation in pain ratings among veterinarians. Women and more recent graduates generally tended to rate pain more highly and treat it more frequently (Dohoo & Dohoo, 1996; Lascelles et al., 1999; Raekallio et al., 2003; Williams et al., 2005; Huxley, 2006; Laven et al., 2009) and increased usage of analgesics among newer veterinarians may well be due to the changes in emphasis of the treatment of pain that have taken place in veterinary medicine during the past 10–15 years (Thomsen et al., 2010). Although the vast majority of respondents generally agree that provision of analgesia is beneficial, and that animals recover more quickly postoperatively if analgesia is provided, the myth still persists that postoperative pain provides some benefit in preventing animals from being too active (Raekallio et al., 2003; Guatteo et al., 2008), even among veterinarians who graduated in the 2000s (Thomsen et al., 2010)—despite the position, held since 1998, of the American College of Veterinary Anesthesiologists that unrelieved pain provides no benefits to animals (ACVA, 1998). Even where a large majority of respondents agree about the importance of treating pain, there is much variation in the circumstances under which pain is treated (Hellyer et al., 1999; Hugonnard et al., 2004; Whay & Huxley, 2005).

Data from repeat Canadian surveys were somewhat encouraging. A 1994 survey showed that approximately 50% of Canadian veterinarians did not use analgesics postoperatively in dogs and cats (Dohoo & Dohoo, 1996). Usage among the other 50% varied with the procedure, and opioids were used almost exclusively, predominantly butorphanol. A similar survey in 2001 showed a marked increase in analgesic usage, with only about 12% of Canadian veterinarians not using analgesics (Hewson et al., 2006b). Given, however, the low usage of perioperative analgesics for many surgeries, together with a continued overreliance on weak opioids (e.g., butorphanol, meperidine) and under usage of strong opioids and NSAIDs, it was evident that postoperative pain was not being managed effectively much of the time.

In the 1994 survey, pain perception scores attributed to different surgical procedures were one of two primary factors affecting analgesic usage (the second was concern about the use of potent opioid agonists in the postoperative period) (Dohoo & Dohoo, 1996). Perception of pain was also a strong predictor of postoperative analgesic usage in 2001 (Hewson et al., 2006a); ratings of pain caused by different surgeries had increased markedly since 1994. In both surveys, veterinarians identified lectures and seminars at the regional level, as well as review articles, as the preferred way to receive continuing education regarding pain and analgesia.

PAINFUL HUSBANDRY PRACTICES IN FARM ANIMALS

The use of at least some degree of perioperative analgesia is fairly widespread in small animal practice (Lascelles et al., 1999; Hugonnard et al., 2004; Hewson et al., 2006b), even if consistency is lacking and there is much room for improvement to provide truly effective, multimodal analgesia. The same cannot be said with large animals, where it remains customary to perform many procedures without anesthesia or analgesia, particularly in North America (Hewson et al., 2007b; Fulwider et al., 2008). However, in some countries analgesia is legally required when carrying out certain husbandry procedures. For example, all the Scandinavian countries now have regulations governing the use of anesthesia and analgesia for procedures such as dehorning and castrating calves (Thomsen et al., 2010). In New Zealand, analgesia is required for castration of cattle over 6 months and for dehorning in those over 9 months (Laven et al., 2009).

Surveys that have compared attitudes toward, and frequency of, pain alleviation in different species pointed out large differences among different animal species undergoing similar operations and among clinical conditions that received equal pain ratings (Hellyer et al., 1999; Raekallio et al., 2003). Even though there is no physiological basis for this differentiation, the discrepancy between practice in companion and production animals is pronounced (Stookey, 2005).

Roadblocks to Treating Pain in Farm Animals

There are many practices carried out routinely in the management of livestock and poultry that cause pain and distress (e.g., castration, tail docking, dehorning, branding, beak trimming). Many of these husbandry procedures are carried out on very young animals (e.g., tail docking in piglets and lambs, beak trimming in poultry); yet there is mounting evidence that such tissue damage early in life may program the animal to a lasting state of somatosensory sensitization and increased pain (Viñuela-Fernández et al., 2007).

Cost–benefit analyses of performing such procedures as an aid to management have too often ignored the costs to the animals themselves in terms of pain and suffering (Hewson, 2006). Increasingly, the public expects pain relief to be provided to farm animals (Phillips et al., 2009; Whay & Main, 2009), yet there are economic, practical, and regulatory constraints, such as the cost of treatment relative to the monetary value of the individual animal, limited availability of licensed analgesic drugs in food animals, and concern about drug residues and food safety (Viñuela-Fernández et al., 2007; Mellor et al., 2008a).

In considering a harm/benefit analysis of husbandry procedures, we should first attempt to minimize the harm (Weary et al., 2006) by asking questions such as:

1. Is the procedure necessary? Is it justified in terms of direct benefit to the animals and/or to the farming enterprise? For example hot iron branding is a cause of avoidable pain to animals and yet, since 2005, a US trade rule has required that all feeder cattle entering the United States from Canada be branded, despite the fact that Canadian cattle for export already bear an ear tag traceable to the farm of origin through the Canadian Cattle Identification infrastructure (Whiting, 2005). Is there another way of achieving the same end, for example, the development of polled breeds to eliminate the need for dehorning calves or immunocastration in calves, piglets, and lambs (Stafford & Mellor, 2009)?

2. What harms are caused, how bad are they, can they be avoided or reduced (e.g., through treatment of pain)?

3. What are the availability, cost, effectiveness, and ease of administration of pain-relieving drugs? Are there adverse effects or residues? Is administration by a veterinarian required?

Husbandry practices with no benefits for animals or farmers may become entrenched. For example, studies have shown no benefits of tail docking in dairy cows, and yet this practice, which has been shown to cause acute and chronic pain, as well as increased fly numbers, and to which the American and Canadian Veterinary Medical Associations are officially opposed (AVMA, 2009, CVMA, 2010), is still widespread in the United States (Fulwider et al., 2008).

The recognition of pain in species such as cattle and sheep may be more difficult because, as prey species, there was strong evolutionary pressure to mask signs of pain and associated weakness (Phillips, 2002; Rutherford, 2002). A large European survey describing pain management practices in cattle (Guatteo et al., 2008) showed very high variability among veterinarians in the knowledge of and sensitivity to pain in cattle. Again, awareness of and ability to assess an animal's pain were critical to the decision on whether to treat pain. In a similar survey in the United Kingdom, cattle practitioners who did not use analgesics assigned significantly lower pain scores to painful procedures or conditions (Huxley, 2006).

In such studies, veterinarians expressed the concern that producers would be unwilling to pay additional costs of providing analgesia (Whay et al., 2005; Huxley, 2006; Hewson et al., 2007a; Guatteo et al., 2008). However, a follow-up study (Huxley & Whay, 2007) showed that, for a significant minority of cattle farmers, the cost of providing analgesia may not be a barrier. For castration and dehorning, for example, 40% and 25% of respondents, respectively, were prepared to pay additional fees sufficient to cover the cost of appropriate analgesic drugs (local anesthesia and NSAIDs). Fifty-three percent of farmers surveyed agreed with the statement Veterinary surgeons do not discuss controlling pain in cattle with farmers enough.

As well, there are costs to NOT providing analgesia. Apart from causing animal suffering, pain can cause significant economic losses (Denaburski & Tworkowska, 2009; Whay & Main, 2009; Grandin, 2009). Yet, a UK study (Leach et al., 2010) showed that, despite a high prevalence of lameness in dairy cows (36% in farms surveyed in 2006–2007), the majority of farmers did not perceive lameness to be a problem on their farm, and underestimated the cost of pain to production.

Management of pain is dependent on the stockperson (or animal caregiver) and the veterinarian. Effective pain management requires recognition of the pain, provision of an environment where the animal can recover, and knowledge about and provision of appropriate analgesic drugs. The ways in which an animal is handled and cared for can exacerbate or mitigate pain and distress. Studies in all major farm animal species have confirmed a strong relationship between the methods used in handling animals, the degree of fear the animals show toward people, and the productivity of the farm (Rushen & Passillé, 2009). For example, a large study of US dairy farms showed lower somatic cell counts in the milk and tendencies to lower percentages of lame cows and shorter calving intervals on farms where the cows were more willing to approach the observer (Fulwider et al., 2008).

A special issue of Applied Animal Behaviour Science, Pain in Farm Animals, summarizes current knowledge about addressing many of the major causes of such pain, for example, disbudding and dehorning in cattle (Stafford & Mellor, 2011a), castration in pigs and other livestock (Sutherland & Tucker, 2011), identification and prevention of intra- and postoperative pain (Walker et al., 2011), and pain issues in poultry (Gentle, 2011).

THE WAY FORWARD

There have been many advances in the understanding of and ability to treat pain in animals in recent decades. We have the knowledge to effectively manage perioperative pain through multimodal analgesia and there are practical resources available to assist veterinarians to do so (Tranquilli et al., 2004; Cracknell, 2007; Flecknell et al., 2007; Lemke & Crook, 2011). There are published recommendations for managing painful procedures in large animals (Lemke et al., 2008; Stafford & Mellor, 2011b), although there are still many constraints. The management of chronic pain continues to present a challenge.

The widespread finding that a veterinarian's perception of pain is a significant predictor of analgesic usage is a major concern, especially considering pain ratings vary so markedly. A persuasive case is made in pediatric medicine against allowing personal beliefs about the experience of pain to prevent optimal recognition and treatment of pain for all children (Hagen et al., 2001). Veterinary practitioners must adopt the same approach for animals.

Veterinarians commonly feel their knowledge of issues related to recognition and management of pain is inadequate, and are interested in continuing education opportunities to address this lack. There is a great deal of information available on assessment and management of pain, which needs to be better communicated to veterinary students and veterinarians.

So what can veterinarians do to better manage pain in animals? Veterinarians working with all species should avail themselves of continuing education regularly to ensure they have current knowledge about recognizing, assessing, and managing pain. Veterinarians working with large animals should ensure that they inform farmers of the strategies available to mitigate pain associated with production practices and with chronic conditions, and of the resulting benefits to the animal and to the bottom line. And veterinarians, as a profession, can work with other stakeholders, as expected of them by society as advocates for animals, to address regulatory, technological, and economic constraints.

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2

Anatomy, Physiology, and Pathophysiology of Pain

Yael Shilo and Peter J. Pascoe

Pain in animals has been defined as an aversive sensory and emotional experience representing an awareness by the animal of damage or threat to the integrity of its tissues; it changes the animal's physiology and behavior to reduce or avoid damage, to reduce the likelihood of recurrence, and to promote recovery (Molony & Kent, 1997).

The ability to react to environmental change is crucial for the survival of an organism, and an essential prerequisite is the capacity to detect and respond to aversive stimuli. Primary afferent nerve fibers provide information to the central nervous system (CNS) about the environment and also about the state of the organism itself. Incoming non-noxious input from the periphery is important for discerning fine discriminative touch, pressure, and position in space. Most animals have dedicated sensory afferents that respond to noxious stimuli. These nociceptive afferents are described by the International Association for the Study of Pain (IASP) as preferentially sensitive to a noxious stimulus or to a stimulus which would become noxious if prolonged (Wall et al., 2006; Smith & Lewin, 2009). Information about a noxious event in the periphery can initiate a protective reflexive withdrawal event (Westlund, 2005; Smith & Lewin, 2009).

Nociception, derived from the Latin nocere meaning to hurt/harm, is the name given to the process by which organisms detect potentially or actually damaging stimuli and the transmission of that information to the brain. It is important to differentiate nociception from pain, which always encompasses an emotional component. Nociceptor activation in and of itself does not necessarily result in pain (Julius & Basbaum, 2001; Muir & Woolf, 2001; Smith & Lewin, 2009; Basser, 2012).

Noxious input is transmitted to the brain through specialized receptors, fibers, and neurons, and processing occurs at many levels (Figure 2.1). Sensory processing includes

Transduction: the conversion of noxious stimuli into an action potential at the level of the specialized receptors or free nerve endings.

Transmission: the propagation of the action potentials by primary afferent neurons to the spinal cord.

Modulation: the process by which nociceptive information is augmented or inhibited.

Projection : the conveyance of nociceptive information through the spinal cord to the brain (to the brainstem and thalamus and then to the cortex).

Perception: the integration of the nociceptive information by the brain, or, in other words, the overall conscious, emotional experience of pain (Muir & Woolf, 2001; Westlund, 2005; Muir, 2009).

Figure 2.1 Pathways involved in nociception. Noxious stimuli (mechanical, chemical, thermal) are transduced into electrical signals that are transmitted to the spinal cord, where they are modulated before being relayed (projected) to the brain for final processing and awareness (Reprinted from Muir, W.W., 3rd. (2009). Physiology and Pathophysiology of Pain, in: J.S. Gaynor & W. W. Muir, 3rd (eds). Handbook of Veterinary Pain Management, p. 14. Copyright MOSBY Elsevier (2009). Reproduced with permission from Elsevier.

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NOCICEPTORS

Activation of nociceptors requires that adequate stimuli depolarize peripheral terminals (producing a receptor potential) with sufficient amplitude and duration. This ensures that despite any attenuation and slowing of the action potential (by passive propagation), information such as stimulus intensity will be encoded in the resulting train of impulses (Dubin & Patapoutian, 2010).

Nociceptive neurons that detect chemical stimuli have a distinct expression of ion channel systems or transduction channels, including transient receptor potential (TRP) ion channels, acid-sensing ion channels (ASIC), purinoceptors, serotonin receptors, and sodium, calcium, and potassium channels (Wall et al., 2006). Agents such as protons or capsaicin directly depolarize nociceptive neurons by triggering the opening of cation channels permeable to sodium and/or calcium. In contrast, agents such as bradykinin and nerve growth factor (NGF) act on G protein-coupled receptors and receptor tyrosine kinase, respectively, to initiate intracellular signaling cascades that, in turn, sensitize depolarizing cation channels to their respective physical or chemical regulators. Other agents, such as glutamate, acetylcholine (ACh), and adenosine triphosphate (ATP), activate ion channels and G-protein-coupled receptors to produce a spectrum of direct and indirect effects on nociceptor membrane potentials (Caterina et al., 2005). This chapter will focus on several important transduction channels; however, it is beyond the scope of this chapter to discuss all of these.

Transient Receptor Potential Ion Channel

The TRPs have emerged as a family of principal transducing channels on sensory neurons, and are classified according to their primary amino acid sequence (rather than according to their selectivity or ligand affinity), as their properties are heterogeneous and their regulation is complex. The transient receptor potential vanilloid (TRPV) channels were first named vanilloid receptors after the active vanillyl structure in the family of compounds that activate these channels. The TRPV1 is a ligand-gated, nonselective cation channel with a preference for Ca²+, which is also activated by noxious stimuli including heat (>43°C), protons, pH < 5.9, and various peptides. Upon opening, Transient Receptor Ion Channel (in particular, Ca²+) flow into the cell and depolarize it. The TRPV1 receptor is predominantly expressed in sensory neurons, and is believed to play a crucial role in temperature sensing and nociception (Caterina et al., 2000; Wall et al., 2006; Rohacs et al., 2008; Vriens et al., 2009; Chung et al., 2011; Schaible et al., 2011). Disruption of the TRPV1 gene in mice eliminates or severely reduces the responses to vanilloid compounds, acid, and heat (>43°C) (Caterina et al., 2000). Thermosensitive TRP channels respond to a wide range of ambient temperatures and may account for the detection of all commonly encountered thermal stimuli, from noxious cold to noxious heat. For example, TRPA1 is sensitive to temperatures less than 17°C, TRPM8 to temperatures of 8°C–26°C, TRPV4 to temperatures over 27°C, TRPV3 to temperatures over 31°C, TRPV1 to temperatures over 43°C, and TRPV2 to temperatures over 52°C (Wall et al., 2006).

Capsaicin, the hydrophobic compound that lends hot capsicum peppers their pungency, is one of a family of structurally related compounds isolated from plants and animals that are essentially sensitizers at TRPV1 because they act by decreasing the thermal physiological activation threshold of TRPV1. Nevertheless, because these compounds bind directly to TRPV1 they are considered agonists or direct activators of this channel, resulting in pain sensation when administered subcutaneously. However, TRPV1-containing neurons can be rendered insensitive to further painful stimuli through receptor desensitization in response to capsaicin, which can result in a generalized lack of responsiveness of this receptor to further noxious stimuli (Caterina et al., 2005; Vyklicky et al., 2008; Vriens et al., 2009; Rosenbaum et al., 2010; Chung et al., 2011). This is the rationale for the topical application of capsaicin and other vanilloids in the treatment of some painful conditions, as capsaicin causes persistent functional desensitization of polymodal primary nociceptors after repeated or prolonged application. This desensitization is suggested to have multiple mechanisms of action and likely involves increasing intracellular free Ca²+ concentrations. The Ca²+ influx activates Ca²+-sensitive phospholipase C (PLC), leading to depletion of phosphatidylinositol 4,5-bisphosphate (PIP2), which leads to diminished channel activity. The calcium sensor calmodulin has also been implicated in desensitization, directly and indirectly, by activating the protein phosphatase calcineurin. ATP may also play a role in this complex process. This TRPV1 desensitization depends on the channel concentration and duration of exposure to capsaicin, and may represent a feedback mechanism protecting the cell from toxic Ca²+ overload (Leffler et al., 2008; Rohacs et al., 2008; Vyklicky et al., 2008).

Although the role of TRPV1 has been primarily studied in cutaneous pain models, it is evident that TRPV1 is involved in nociception not only in skin but also in musculoskeletal and visceral tissues. Expression of TRPV1 has also been demonstrated in the spinal cord, mainly laminae I and II of the dorsal horn (Caterina et al., 2000; Rohacs et al., 2008; Chung et al., 2011).

Sensory Neuronal Sodium Channel

When noxious stimuli result in adequate depolarization, voltage-gated sodium channels open and action potentials are generated. Voltage-gated sodium channels (Nav) are complex transmembrane proteins that allow the rapid influx of sodium underlying the depolarizing upstroke of action potentials in excitable cells. Nav typically open (activate) within a millisecond in response to membrane depolarizations, leading to a regenerative all-or-none depolarization typical of action potentials in neurons (Cummins et al., 2007; Schaible et al., 2011).

Nine distinct Nav α-subunits (Nav 1.1–1.9) have been cloned from mammals. Many of the Nav 1 α-subunits have specific developmental, tissue, or cellular distributions: Nav 1.4 is almost exclusively expressed in skeletal muscle; Nav 1.5 is predominantly expressed in cardiac muscle; Nav 1.3 is predominantly expressed in immature neurons and is normally found at very low concentrations in adult neurons. However, under certain conditions Nav 1.3 expression is upregulated in adult neurons, and this may play a role in altered pain sensation. Adult CNS neurons may express combinations of Nav 1.1, Nav 1.2, and Nav 1.6. Adult dorsal root ganglia (DRG) sensory neurons can express combinations of Nav 1.1, Nav 1.6, Nav 1.7, Nav 1.8, and Nav 1.9, and peripheral primary sensory afferents express Nav 1.7, Nav 1.8, and Nav 1.9 (Cummins et al., 2007; Qi et al., 2011).

Tetrodotoxin (TTX), a toxin found in the liver of the puffer fish, is a highly selective blocker of CNS and skeletal muscle sodium currents but a relatively weak blocker of cardiac muscle sodium currents, emphasizing that distinct proteins generate the sodium currents in different tissues. While CNS neurons express relatively homogeneous currents exhibiting rapid activation, rapid inactivation, and high sensitivity to TTX, DRG neurons express more complex currents that contain both rapidly inactivating TTX-sensitive (TTX-S) components and slowly inactivating TTX-resistant (TTX-R) components. The slower TTX-R currents are thought to prolong the duration of the action potentials, thereby modulating neurotransmitter release at the nerve terminals. The sodium channels Nav 1.1, Nav 1.3, Nav 1.6, and Nav 1.7 are TTX-S, whereas Nav 1.8 and Nav 1.9 are TTX-R (Cummins et al., 2007; Schaible et al., 2011).

The resting potential of DRG neurons is about −60 mV. After small depolarizations (at −50 to −40 mV), Nav 1.7 opens and this initial Na+ influx brings the neuron closer to the membrane potential for elicitation of an action potential. The Nav 1.8, which is expressed only in sensory neurons and largely restricted to nociceptive neurons, opens at −30 to −20 mV, that is, when the cell has been predepolarized (e.g., by Nav 1.7), and provides about 80% of the inward current of the upstroke of the action potential in DRG neurons. In particular, Nav 1.8 is located primarily on the terminals and the cell body, suggesting a role in action potential initiation at the sensory terminal of nociceptive neurons. It also mediates repetitive action potentials during persistent membrane depolarization (e.g., in the presence of inflammatory mediators). While Nav 1.7 and Nav 1.8 are directly involved in the generation of the action potential, Nav 1.9 influences the threshold for action potentials. The channel opens around −60 mV and conducts persistent Na+ currents at voltages below the threshold for action potential generation, thus regulating the distance between membrane potential and threshold; it does not contribute to the upstroke of the action potential (Schaible et al., 2011).

Acid-sensing Ion Channel

Nociceptive neurons can also be activated by reductions in extracellular pH, as is often observed in tissue injury, inflammation, or ischemia. One group of ion channels implicated in acid-evoked nociception is the ASIC family of proteins, which are highly selective Na+ channels expressed in DRG neurons. It is believed that ASICs are most important in skeletal muscle and the heart, in which impaired circulation causes immediate pain (Caterina et al., 2005; Schaible et al., 2011).

NOCICEPTIVE AFFERENTS

The cell bodies of nociceptive afferents are located in the DRG and the trigeminal ganglion and extend central axonal endings into the spinal gray matter to communicate with second-order neurons in the dorsal horn (terminating predominantly in laminae I, II, and V) or the trigeminal subnucleus caudalis (Vc) in the caudal medulla, respectively (Westlund, 2005; Smith & Lewin, 2009; Dubin & Patapoutian, 2010).

Nociceptive afferents may be subclassified with respect to the presence or absence of myelination, the modalities of stimulation that evoke a response (i.e., thermal, mechanical, or chemical), the response characteristics (rapid versus slow response), and the distinctive chemical markers (e.g., receptors expressed on the membrane). The most common means of classification of primary sensory neurons is based on the conduction velocity of their peripheral axons, which is directly related to the axon diameter and the degree of axonal myelination. Based on peripheral conduction velocities, primary sensory neurons are routinely divided into different groups: Aβ, Aδ, and C (Table 2.1) (Caterina et al., 2005; Wall et al., 2006; Dubin & Patapoutian, 2010).

Table 2.1 Primary afferent axons

Table02-1

Nociceptive afferents responding to thermal (heat, H and cold, C), mechanical (M), and chemical stimuli (polymodal) are the most common C-fiber type observed in fiber recordings (C-MH, C-MC, C-MHC). C fibers responsive to noxious heat (C-H; ∼10% of C-nociceptors) play a major role in heat sensation. A-δ fiber nociceptors are predominantly heat- and/or mechanosensitive (A-MH, A-H, A-M); however, sensitivity to noxious cold is also observed (Smith & Lewin, 2009; Dubin & Patapoutian, 2010). See Table 2.1 for detailed comparison among fiber types (Julius & Basbaum, 2001; Smith & Lewin, 2009).

Approximately half of Aδ-fiber nociceptors and 30% of C-fiber nociceptors have very high mechanical thresholds (>6 bar = 600 kPa = 60 g/mm²) or are unresponsive to mechanical stimuli. This class of nociceptors is termed mechanically insensitive afferents, or silent nociceptors. However, after exposure to inflammatory mediators, some of these insensitive fibers become responsive to mechanical and/or heat stimuli, a process known as sensitization (Wall et al., 2006; Smith & Lewin, 2009; Dubin & Patapoutian, 2010).

Primary sensory neurons are often classified according to their expression of molecular markers, and two broad categories of unmyelinated nociceptors (C fibers) have emerged: peptidergic cells that express calcitonin gene-related peptide (CGRP) and substance P (SP), and are sensitive to neural cell derived-NGF; and nonpeptidergic cells that lack these peptides but express the receptor tyrosine kinase, have binding sites for the plant isolectin B4, and are responsive to glial cell line-derived neurotrophic factor. The central projections of these two nociceptor types are segregated in different laminae of the dorsal horn. Peptidergic neurons are thought to be involved with inflammatory pain and release SP and CGRP from their sensory endings, inducing vasodilation, plasma extravasation, and other effects, thus producing a neurogenic inflammation (Julius & Basbaum, 2001; Golden et al., 2010; Schaible et al., 2011). The nonpeptidergic neurons may be involved in neuropathic pain, that is, pain that arises from damage to the CNS or peripheral nervous system (Willcockson & Valtschanoff, 2008; Golden et al., 2010).

SPINAL CORD

A transverse section of the spinal cord shows a central canal filled with cerebrospinal fluid (CSF) surrounded by the gray matter—a region containing mainly the cell bodies of neurons and also dendrites, axons, and glial cells and the peripheral white matter—a region containing mostly axons and also glial cells (Figure 2.2).

Figure 2.2 A transverse section of the spinal cord.

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White Matter

The white matter is divided into three columns (or funiculi) by the horns of the gray matter: dorsal, lateral, and ventral (Figure 2.2). Ascending or descending axons that have a common function typically travel together and are identified as a tract, which is usually named for its origin and termination. The main ascending tracts associated with nociception in animals are the spinothalamic, the spinocervicothalamic (also termed spinocervical), and the postsynaptic dorsal column (Figure 2.3). The relative importance of these nerve tracts in transmitting noxious sensory information to the brain varies among species. For example, the spinothalamic pathway, which is the major ascending nociceptive pathway in rodents and primates, is thought to be less important in carnivores; however, the spinocervicothalamic tract is regarded as the dominant nociceptive pathway in carnivores (Fletcher, 1993). The postsynaptic dorsal column conveys information about visceral pain.

Figure 2.3 The main ascending nociception pathways of the spinal cord in animals.

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The propriospinal system (Figure 2.3) projects throughout the white matter and for varied distances both rostrally and caudally. Included are propriospinal fibers that travel between cervical and lumbosacral cord enlargements, long descending propriospinal tract (LDPT) axons, as well as short propriospinal tract axons that either ascend or descend for a few segments throughout the length of the cord. The propriospinal system is important in mediating reflex control in response to noxious stimuli, and in coordination during locomotion (Conta & Stelzner, 2004).

The dorsolateral fasciculus or the tract of Lissauer is situated between the dorsal horn and the surface of the spinal cord (Figure 2.3). It consists of overlapping ascending and descending axonal branches of small, primary afferent neurons, which respond to noxious, thermal, or tactile stimuli (Fletcher, 1993).

The Gray Matter

The gray matter is divided into three main zones: the dorsal horn, the ventral horn, and the lateral horn or intermediolateral column. The dorsal horn is comprised of sensory nuclei that receive and process incoming somatosensory information. The lateral horn is limited to the thoracic and upper two lumbar spinal cord segments. It contains preganglionic sympathetic neurons whose axons exit the spinal cord via the ventral roots. Preganglionic parasympathetic neurons are located in a comparable region of the gray matter at the S2–S4 levels of the spinal cord. The ventral horn comprises motor neurons that innervate skeletal muscle (Figure 2.2) (Goshgarian, 2003; Watson & Kayalioglu, 2009).

The distribution of cells and fibers within the gray matter of the spinal cord exhibits a pattern of lamination, which led Rexed in 1952 to propose a new classification based on 10 layers (laminae) (Figure 2.4). This classification is useful because it is related more accurately to function than the previous classification scheme, which was based on major nuclear groups. In general, the first six laminae compose the dorsal horn.

Figure 2.4 The Rexed laminae distinguish 10 different layers in the spinal gray matter on the basis of the characteristics of their neurons. The dorsal horn contains laminae I–VI, while the ventral horn, comprising the motor neurons, contains laminae VII–IX. Lamina X surrounds the central canal.

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Lamina I, also known as the marginal layer, forms a thin sheet covering the dorsal aspect of the dorsal horn and contains projection neurons, with axons that travel rostrally in the white matter and convey information to various parts of the brain, and interneurons, with axons that remain in the spinal cord and contribute to local neuronal circuits. The projection cells are generally larger than the interneurons and a few particularly large projection neurons are known as giant marginal cells of Waldeyer.

Lamina II is known as the substantia gelatinosa because the lack of myelinated fibers within it gives it a translucent appearance in unstained sections. Virtually all of the neurons in this lamina are small interneurons and these are particularly densely packed in its outer part.

Lamina III also contains a high density of neurons. Most are small interneurons, which are generally somewhat larger than those of lamina II, but scattered large projection neurons are also present in this lamina.

Laminae IV–VI are more heterogeneous, with neurons of various sizes, some of which are projection cells. The borders between these laminae are difficult to place with certainty. (Goshgarian, 2003; Wall et al., 2006).

Lamina VII contains all visceral motor neurons, whose axons extend to autonomic ganglia.

Laminae VIII and IX are in the ventral horn. Lamina VIII is composed of interneurons, whereas lamina IX is comprised of individual clusters of α motor neurons. The axons of these neurons innervate mainly skeletal muscle.

Lamina X is comprised of small neurons surrounding the central canal and contains neuroglia (Goshgarian, 2003; Watson & Kayalioglu, 2009).

C fibers and Aδ fibers convey nociceptive information principally to the superficial (laminae I/II) and deep (V/VI) laminae of the dorsal horn as well as to the circumcanular lamina X. Aβ fibers transmit non-noxious information to laminae III–VI (Millan, 2002).

Dorsal Horn Neurons

The cell bodies of primary sensory neurons that innervate the limbs and trunk are located in the DRG. Their axons bifurcate within the ganglion and give rise to a peripheral branch that innervates various tissues, and a central branch that travels through a dorsal root to enter the dorsal horn of the spinal cord, where it forms synapses with second-order neurons.

These second-order neurons include projection cells, interneurons, and propriospinal neurons. Propiospinal neurons transfer inputs from one segment of the spinal cord to another. Although their role in nociception is poorly understood, propriospinal neurons act as a multisynaptic pathway transferring information to the brain, and, in addition, have a major role in controlling locomotion and organizing coordinated reflex responses (Sandkuhler et al., 1993; Wall et al., 2006; Cowley et al., 2008).

Interneurons make up the great majority of the neuronal population in the dorsal horn, and can be divided into two main morphological classes: the islet cells are found throughout lamina II and are thought to be inhibitory interneurons, which use γ-aminobutyric acid (GABA) and/or glycine as a transmitter, and the stalked cells that are found primarily at the junction between laminae I and II and are reported to serve as either inhibitory interneurons or excitatory interneurons, which use glutamate. Interneurons play a critical role in modulating nociceptive signals from the primary afferents and conveying the information to projection neurons (Todd & Ribeiro-Da-Silva, 2005; Wall et al., 2006; Maxwell et al., 2007). The projection neurons and the interneurons that encode nociceptive information can be divided into two major classes: wide dynamic range neurons (WDR; also called convergent), which are activated by weak mechanical stimuli but respond with increasing discharge frequencies as the intensity of the mechanical stimulus increases, and nociceptive-specific neurons, that respond only to intense noxious forms of mechanical, thermal, or chemical stimuli (Millan, 2002; Todd & Ribeiro-Da-Silva, 2005; Wall et al., 2006). The WDR neurons are important substrates for the expression of descending controls, and their sensitization by repetitive, nociceptive stimulation plays a key role in the induction of long-term inflammatory and/or neuropathic pain states (Millan, 2002).

Dorsal Horn Synaptic Transmission

Dorsal horn nociceptive neurons possess a rich diversity of receptors whose activation regulates neurotransmitter release and subsequent activation of second order neurons. Excitatory receptors include the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) classes of ionotropic glutamate receptors and the metabotropic glutamate receptors. These receptors act via multiple intracellular mechanisms including the activation of G-proteins, which activates PLC, resulting in suppression of K+ currents and enhancement of Ca²+ currents.

The neurokinin-1 (NK1) receptor is another excitatory receptor present throughout the dorsal horn, with the highest concentration in lamina I. The excitatory influence of NK1 receptors upon neuronal activity is due to the activation of G-proteins and PLC, resulting in suppression of K+ currents and enhancement of Ca²+ currents. SP is probably released from primary afferents at extrasynaptic sites and acts on NK1 receptors on the projection neurons through volume transmission. Volume transmission involves activation of receptors via extrasynaptic diffusion of neurotransmitter, allowing amplification of the signal by transmission to multiple neurons (Zoli et al., 1999; Millan, 2002; Wall et al., 2006; Rice & Cragg, 2008).

Within the dorsal horn the terminal of the primary afferent neuron synapses with a dorsal horn neuron and, depending on the intensity of stimulation, this may be sufficient to produce a postsynaptic output. Like the vast majority of fast excitatory synapses throughout the CNS, most presynaptic excitatory terminals in the dorsal horn release glutamate, which activates ionotropic AMPA, kainate, and NMDA receptors, and the G-protein-coupled metabotropic family of receptors on the postsynaptic neurons. The excitatory postsynaptic potentials (EPSPs) resulting from single presynaptic action potentials are caused primarily by activation of the AMPA and kainate subtypes of the ionotropic glutamate receptor, and typically last for only a few milliseconds. This type of fast excitatory synaptic transmission occurs even at synapses of slow nociceptor C-fiber primary afferents. With low-frequency activation of nociceptors produced by mild noxious stimuli, these EPSPs signal to dorsal horn neurons the onset, duration, intensity, and location of noxious stimuli in the periphery.

GABA receptors are also expressed by sensory neurons, and play a crucial and complex role in inhibition of nociceptive processing. These receptors are mainly located in the superficial laminae, and include two classes of receptors: GABAA receptors are concentrated on the postsynaptic membrane of inhibitory synapses, are comprised of pentameric ion channels, and exert their inhibitory action by increasing permeability to chloride anions. GABAB receptors are localized to presynaptic terminals and are heterodimers that inhibit adenylyl cyclase (AC) via G-protein activation, resulting in increased K+ currents and suppression of Ca²+ currents (Millan, 2002; Wall et al., 2006).

The three main opioid receptors (μ, δ, and κ) are located on primary sensory neurons, and α-2 adrenergic receptors are localized at the central terminals of peptidergic fibers. Activation of opioid receptors and α-2 receptors inhibits AC, which enhances K+ currents and suppresses Ca²+ currents, thus inhibiting neuronal excitability (Millan, 2002; Wall et al., 2006). A coexpression of δ-opioid receptors and α-2A adrenergic receptors on SP-expressing primary afferent fibers was shown in rat dorsal horn and skin. This may underlie the mechanism of the synergistic interaction observed in vivo when agonists of both receptors are coadministered spinally (Riedl et al., 2009).

Fast inhibitory postsynaptic potentials (IPSPs) hyperpolarize the postsynaptic membrane and are produced by chloride currents mediated by glycine and GABA acting on the ionotropic glycine and GABAA receptors. The GABAB receptor is a G-protein-coupled receptor and produces slower-onset and longer-lasting inhibition, predominantly presynaptically (Wall et al., 2006).

Glial and Immunocompetent Cells in the Dorsal Horn

It is important to discuss the influence of non-neuronal units in the dorsal horn. These include resident glial cells (astrocytes, oligodendrocytes, and immunocompetent microglia) and immigrant immunocompetent T cells, which may infiltrate the dorsal horn following damage to the spinal cord, primary afferent fibers, or peripheral tissue, and subsequent loss of blood–brain barrier integrity. The function of glial cells is subject to modulation by glutamate, ACh, SP, GABA, serotonin, norepinephrine, adenosine, and other transmitters originating in descending pathways, primary afferent fiber terminals, and dorsal horn neurons (Millan, 2002). Of particular note is the role of glial membrane transporters in regulating the accumulation or reuptake of the three major amino acid neurotransmitters in the CNS: glutamate, GABA, and glycine. This function of glial cells suggests their involvement in the regulation of synaptic activity. Glial transporters regulate the clearance of neurotransmitters released by neurons (e.g., glial transporters play a critical role in protecting neurons from glutamate-induced neurotoxicity), and also release neuroactive compounds in response to multiple stimuli (Gadea and Lopez-Colome, 2001a; Gadea and Lopez-Colome, 2001b; Gadea and Lopez-Colome, 2001c; Millan, 2002).

Glial cells regulate neuronal cholinergic transmission via