Transduction

Intense thermal, mechanical, and chemical stimuli are detected by a subpopulation of peripheral nerve fibers called nociceptors. Nociceptors are excited only when stimuli reach a noxious range (i.e., low sensitivity, high threshold properties). Historically, nociceptors have been described as unmyelinated nerve endings located throughout the body tissues. Specialized cutaneous glial cells with extensive processes form a mesh‐like network within the subepidermal border of the skin and are involved with conveying mechanical and thermal sensitivity [4]. There are two major classes of nociceptors; myelinated medium diameter fibers (A‐delta [Aδ]‐fibers) that mediate acute, localized, fast pain, and unmyelinated, small diameter fibers (C‐fibers) that convey less localized, dull or slow pain. Nociceptors and the specialized glial meshwork recognize environmental (thermal, mechanical, chemical) energy and transform it into electrochemical signals.

Transmission

The electrochemical signals are propagated as action potentials from the periphery to the dorsal horn of the spinal cord via afferent, sensory nerve fibers. Activation of the sensory nerve endings primarily causes the release of glutamate or substance P (SP) into the synaptic cleft. The postsynaptic effect of glutamate/SP is mediated by several inotropic receptors, chiefly α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA), kainite, and NMDA receptors.

Primary Modulation

The initial processing of afferent noxious stimuli occurs in the spinal cord via a complex structure of second‐order neurons. The gray matter within the spinal cord is composed of cells responsible for the transmission of specific nerve fibers. Lamina I (marginal layer) contains neurons that are generally responsive to thermal input from Aδ‐ and C‐fibers. Lamina II (substantia gelatinosa) is generally responsive to noxious stimulation from Aδ‐ and nonpeptidergic C‐fibers. Lamina V neurons receive both innocuous A‐beta (Aβ)‐input (touch) and high‐threshold Aδ‐ and C‐fibers (noxious); therefore, this region is referred to as having a wide dynamic range (WDR). Although Lamina X is not physically part of the dorsal horn, it does receive nociceptive input, primarily from the visceral regions [5]. Activation of the second‐order neurons produces both excitatory and inhibitory effects [6]. For example, nociceptive‐specific C‐fibers converge on the WDR of Lamina V which project to inhibitory interneurons. The inhibitory neurons reduce nociceptive transmission either by reducing activity in the WDR or inhibiting the release of neurotransmitters from C‐fibers [4]. Although the primary projection of afferent nerve fibers is in the spinal cord segment of entry, collateral interneuron spread can send excitatory impulses to adjacent segments, resulting in multiple dermatomes being affected. In addition, neuroplasticity within intraneuronal communications and duplicated noxious sensory information across multiple spinal segments can further result in somatic‐visceral and visceral‐somatic reflexes (see the section titled “Central Sensitization”).

Peripheral Sensitization (Wind‐Up)

Tissue injury with subsequent inflammation can eventually elicit alterations in nociceptive afferent responses. Acceleration of ongoing (spontaneous) presynaptic afferent neurons innervating the site of tissue injury and inflammation can potentiate activation of silent nociceptors and conversion of low threshold Aβ‐ to behave like Aδ‐fibers. There are multiple factors leading to altered peripheral afferent response characteristics. Changes in the local chemical microenvironment associated with inflammation drive the alteration and increased responsiveness in peripheral nociception within the injured tissue. Tissue damage and plasma extravasation result in an “inflammatory soup” consisting of factors including hydrogen and potassium ions, local inflammatory cells, prostaglandins, leukotrienes, histamine, serotonin, bradykinin, cytokines (tumor necrosis factor alpha [TNF‐α]), and nerve growth factor. Locally released factors activate C‐fibers which are perceived as slow or dull pain sensation. The degree of receptor activation is directly related to the concentrations and composition of local factors. The combination of a concentrated “inflammatory soup” coupled with the activation of silent fibers, conversion of low‐threshold Aβ‐fibers, and peripheral afferent axon growth (budding) relates to peripheral sensitization [7]. Peripheral sensitization and intense, monotonic afferent stimuli can result in central summation which then amplifies the degree of pain. Increased peripheral input can lead to “hyperalgesia priming” and/or wind‐up and eventually to central sensitization through long‐term potentiation in the CNS [8]. Changes in peripheral terminal excitability (peripheral sensitization) and the ongoing activity in the pain‐activated afferent sensory nerve result in an increase response within the spinal cord (central sensitization).

Central Sensitization (Wind‐Up)

Dorsal horn WDR neurons have a stimulant‐dependent response to single C‐fiber stimuli. The physiological result of an intense and/or persistent barrage of afferent, C‐fiber stimuli within the spinal cord could result in the amplification of nociceptive messages defined as a pathophysiological pain condition called central wind‐up. The combined effect of peripheral and central wind‐up causes activation of adjacent spinal segments and corresponding dermatomes. The receptive field includes not only the primary area of tissue damage but also surrounding dermatomes, resulting in a debilitating condition called referred pain and/or allodynia. Another consequence of segmental recruitment due to central sensitization is the presence of somatic‐visceral (or visceral‐somatic) reflexes, seen clinically as chronic visceral conditions coexisting with chronic peripheral pain. When internal organs have pathological conditions, somatic zones that are innervated by the same spinal segments can exhibit increased degrees of sensitivity [9, 10]. In humans, this relationship has been seen clinically as pain‐sensitive points on the abdomen and back regions in patients with gastric ulcers. The visceral‐somatic Aδ‐ and C‐fiber stimuli from peripheral afferent nociceptive neurons cause the release of a variety of neurotransmitters including glutamate and SP at the central nerve terminals. Afferent, noxious stimuli at the dorsal horn and subsequent glutamate, and SP activation of AMPA and neurokinin‐1 (NK1) receptors, respectively, are considered one component of physiological nociception. However, high‐intensity and/or persistent WDR C‐fiber input can result in activation of NMDA and NK1 receptors, which increases the amplitude of signaling and responsiveness in the spinal cord segment(s). These neurochemical changes are examples of the neuroplastic properties of the nervous system and highlight the turning point at which the physiologic response to noxious input becomes a hypersensitized, amplified process, resulting in pathological, chronic, and debilitating conditions. Another important property of the nervous system is its memory. Once the condition of central wind‐up nociception occurs, it cannot be “unlearned.”

Chronic or Maladaptive Pain

Chronic or maladaptive pain is pain that lasts beyond 6 months and/or the expected time for tissue healing. Chronic pain is considered an abnormal condition or disease in and of itself. It is pain that no longer serves a protective, life‐sustaining purpose. In fact, chronic pain is debilitating and tends to increase the likelihood of comorbidities and decrease life expectancy [11]. In humans, chronic pain is associated with diabetes mellitus, obesity, hypertension, heart disease, decreased exercise, depression, sleep disturbances, anxiety, and fatigue. These comorbidities reduce the quality of life and obstruct an individual from experiencing a healthy lifestyle. The term “chronic pain” was first used around the 1900s to describe painful human patients that were “often regarded as deluded or were condemned as malingers or drug abusers” [12]. Veterinary medicine still struggles with an objective means of recognizing and treating chronic pain. Unfortunately, it is still problematic for the veterinary industry to agree as to whether animal patients experience chronic pain and how to effectively treat the condition.

Animal patients have almost identical nociceptive physiology and contain all the pain‐processing brain centers as human patients. It would be illogical to conclude that animals do not experience chronic pain in ways like humans. Underrecognized and undermanaged chronic pain may result in death via humane euthanasia years earlier than would otherwise be necessary [13]. Although veterinary medicine has made strides in recognizing acute pain by utilizing semi‐objective pain scores (i.e., Glasgow composite pain scores for dogs and cats, Equine [and other species] Grimace Scales), we still do not have consistent, universal means to recognize chronic pain in our patients. Traditionally, veterinary practitioners have relied almost exclusively on behavior changes as indicators of chronic pain in animal patients. Examples of behaviors related to chronic pain in veterinary patients include diminished exercise or general activity, difficulty in walking, standing, eating, and taking stairs, decreased grooming, and changes in urination and/or defecation [14]. Myofascial palpation is a technique that can aid veterinarians in recognizing chronic pain in their patients. A palpatory examination of the myofascial structure may reveal clinical information that correlates to a chronic, painful condition endured by a veterinary patient. Palpatory examinations include thermal palpation, myofascial palpation, joint palpation, and structure mobility (gait). Myofascial palpatory indicators of chronic pain include trigger points, taut bands, muscle atrophy, temporal mandibular changes, areas on the body with increased and/or decreased temperature, and gait abnormalities with compensatory weight adaptations.

Neuropathic Pain

Neuropathic pain is associated with damage or disease involving the somatosensory nervous system and may or may not be associated with loss of neurological, autonomic, or motor function [15]. In humans, neuropathic pain is described as burning, shooting, stabbing, and/or electric shock sensations which can be continuous or episodic. Neuropathic pain can originate from peripheral nerve damage resulting in neuronal hyperexcitability and spontaneous pathological activity resembling peripheral sensitization described in the preceding text. Peripheral neuropathy can directly contribute to the development of central sensitization. Causes of central neuropathic pain can be related to injury or diseases involving structures associated with the spinal cord.

Central sensitization is almost always a consequence of central neuropathic pain. In fact, some believe that the two types of hypersensitized pain (central wind‐up pain and central neuropathic pain) are practically synonymous. Both central, hypersensitized types of pain are associated with the activation of the NMDA postsynaptic receptors. In addition, both are related to changes in the functional properties of the afferent sensory (nociception and innocuous) and second‐order neurons in the spinal cord. These changes are defined by a reduction of pain threshold and endogenous antinociceptive mechanisms and increased magnitude and duration of responses to noxious input, and innocuous sensory input is perceived as pain sensations [16]. Neuropathic pain is notoriously difficult to manage. In humans, it is estimated that between 40% and 60% of those affected by neuropathic pain achieve partial relief [17]. In addition to analgesics, treatment includes antidepressants, anticonvulsants, and topical applications.

Preventive and Multimodal Analgesia

Balanced anesthesia refers to using two or more anesthetic agents in small doses to provide a summed or greater effect. Preemptive analgesia is a form of pain control dating back to 1913 when Crile realized that postoperative pain improved if regional blocks were administered prior to surgery [18]. In 1986, Wall introduced the concept of preemptive analgesia as a protocol to reduce postoperative pain by administering analgesics preoperatively [19]. In 2011, Katz published an analgesic management protocol called “preventive analgesia” that considers three perioperative phases: preoperative, intraoperative, and postoperative [20]. Preventive analgesia is a pain management system based on the realization that some analgesic interventions or analgesic combinations influence postoperative pain by exceeding the expected drug duration of action [21]. The concept of preventive analgesia has been broadened with increasing knowledge to consider the influence of multiple factors on the generation of central sensitization, with the aim to attenuate the impact of noxious preoperative, intraoperative, and postoperative stimuli [22].

Stay updated, free articles. Join our Telegram channel

Join