Nociceptors are free nerve endings of certain (C and Aδ) primary afferent, or sensory, neurons. They are distributed widely throughout the body, being found in skin, bone, muscle, most internal organs, blood vessels, and meninges. Nociceptors are activated by chemical, thermal, or mechanical stimuli. Examples of noxious stimuli include intense pressure, mechanical stress, heat above 43–45°C, endogenous substances—such as potassium ions, hydrogen ions, and inflammatory mediators (e.g. bradykinin, histamine)—and exogenous substances, such as capsaicin. Nociceptors can respond to one or more type(s) of stimuli and are often classified by the type of stimuli they transduce. Most nociceptors respond to multiple types of stimuli and are thus known as polymodal nociceptors. There also exists a population of “silent” nociceptors that normally have very high activation thresholds. Only after their activation threshold has been lowered by some mechanism can they convert a noxious stimulus into a nerve action potential.

   Activation of nociceptors results in the production of a depolarizing electrical current, or a generator potential, within the neuron terminal. Ion channels expressed in nociceptors, such as those belonging to the transient receptor potential (TRP) family, function to transduce the noxious stimuli. The transient receptor potential vanilloid subtype 1 (TRPV1) is a nonselective cation channel that has been identified in dorsal root ganglia, spinal, and peripheral nociceptive nerve terminals. This receptor can be activated by heat greater than 43°C, low pH, capsaicin, and a variety of other proalgesic substances. Inflammatory mediators such as ATP, bradykinin, trypsin, and some prostaglandins potentiate TRPV1 receptor function by activation of protein kinase signaling pathways within the neuron and subsequent phosphorylation of TRPV1. Recently, the bioactive phospholipid lysophosphatidic acid (LPA), a molecule for which a role in neuropathic pain has been described and whose amounts increase subsequent to tissue injury, has been shown to directly activate TRPV1 receptors. Previously LPA was thought to modulate intracellular pain signaling pathways through action on LPA specific membrane G-protein coupled receptors.

   Additional ion channels have been implicated in directly transducing noxious stimuli, including those activated by changes in mechanical stretch or osmolality, ATP-gated ion channels, and acid-sensing ion channels; however, their exact roles have yet to be fully elucidated.

   Nociceptors have the ability to increase their level of sensitivity following tissue injury or repetitive stimulation. Many channels and receptors expressed by nociceptive neurons are not directly activated by noxious stimuli but instead play important roles in modulating the responses of the primary transducing elements. As already mentioned, transduction of a noxious stimulus creates a generator potential in the nerve terminal. If this generator potential is of sufficient magnitude, it will initiate an action potential in the neuron, which is then transmitted in an all-or-none fashion along the neuron to the spinal cord. Depolarization of the nociceptive nerve terminal has additional effects, such as local release of neurotransmitters, like the neuropeptides substance P and calcitonin gene-related peptide (CGRP). These neuropeptides produce vascular leakage and local edema, contributing to the phenomenon of neurogenic inflammation. Bradykinin can now move into tissues from the plasma out of the now “leaky” vasculature, causing further vasodilation in addition to activating and sensitizing nociceptors. The products of arachidonic acid metabolism, especially prostaglandins, also contribute to this sensitization by having facilitatory actions on nociceptive transduction channels, like TRPV1, and on sodium channels responsible for transmitting action potentials. Inflammatory cell migration, cytokine production, and degranulation of mast cells with local release of histamine and serotonin, all exacerbate this response and cause further release of inflammatory mediators. This sensitized state resulting from a reduction in threshold and increase in responsiveness of nociceptors is known as peripheral sensitization and creates the clinically observed phenomenon of primary hyperalgesia. Not only can intracellular signaling be modified with chronic pain states but also the expression of TRPV1 channels has been shown to be upregulated in neuropathic pain models.

   After nerve injury myelin degenerates, macrophages and neutrophils infiltrate. These changes are accompanied by the release of proinflammatory cytokines, inflammatory mediators, and nerve growth factor—all of which promote the development of hyperalgesia and allodynia.

   The peripheral expression of opioid receptors has been demonstrated to occur during inflammation. These receptors are typically coupled to inhibitory Gi/Go proteins, activation of which leads to the inhibition of voltage-gated calcium channels. The effect of this is to reduce the peripheral nerve terminal calcium ion concentrations subsequent to the creation of a generator potential. This, in turn, reduces the release of neurotransmitters such as substance P. Overall, the effect is to reduce sensitization of nociceptors, thus providing analgesia, in addition to having anti-inflammatory actions.

Primary afferent neurons have cell bodies located within the dorsal root ganglion and some brain stem nuclei, in addition to peripheral and central processes. The electrical signal generated during transduction of a noxious stimulus is transmitted from the peripheral axon as a single action potential or a series of action potentials through the neuron to the spinal cord dorsal horn. Under physiologic conditions, those primary afferent neurons responsible for transmission of noxious stimuli are A-delta and C fibers. Both fiber types are small in diameter; however, A-delta fibers are thinly myelinated, thus faster conducting, and mediate what is typically described as sharp pain, first pain, or superficial pain. C fibers are smaller in diameter and unmyelinated; therefore, they conduct more slowly than A-delta fibers. C fibers are responsible for transmitting the dull or burning second pain sensation, as well as the type of pain sensation referred to as deep pain sensation (nociception).

   Central processes from nociceptive primary afferents terminate in laminae I, II, and IV of the dorsal horn, where they synapse with second-order sensory neurons. These second-order neurons are of two main types: spinal projection neurons and interneurons. Spinal projection neurons innervate higher centers and the interneurons serve a variety of functions, such as providing polysynaptic connections between primary afferent and projection neurons, and spinal modulation of synaptic transmission.

   At their synapses within the spinal cord the primary afferent neurons release two main classes of neurotransmitters: the excitatory amino acids, primarily glutamate, and the neuropeptides, primarily substance P. On the postsynaptic membrane are the target receptors for glutamate, such as NMDA (N-methyl-d-aspartate) and AMPA (α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) receptors, and target receptors for the neurokinins, neurokinin receptor subtypes 1 and 2 (NK1, NK2). These receptors are all ligand-gated cation channels, and as such their activation results in the depolarization of the postsynaptic cell. There are a number of extrasynaptic receptors which function to modulate activity at this synapse. Enhancement of neurotransmitter release by the presynaptic cell is effected by presynaptic NMDA receptors. Alpha-2 adrenergic receptors, opioid receptors, gamma-aminobutyric acidB (GABA_B) receptors, and serotonergic (5HT) receptors are located extrasynaptically on both the presynaptic and postsynaptic cell membranes. Activation of these receptors produces analgesia, presynaptically by inhibiting neurotransmitter release and postsynaptically by hyperpolarizing the cell, making transmission of the noxious stimulus more difficult.

   The responsiveness of second-order sensory neurons to stimuli can be altered by many direct and indirect factors, such that they play a dynamic role in information processing at the spinal cord level. Ongoing nociceptive input sensitizes NMDA receptors in addition to altering intracellular signaling cascades. Local networks of inhibitory and excitatory neurons within the spinal cord (formed by interneurons) modulate the function of both the primary and secondary sensory neurons. Spinal cord inhibitory neurons use GABA and glycine as their major neurotransmitters. Both neurotransmitters act as ligands for ionotropic receptors that function as chloride channels (GABA_A and GABA_C and glycine receptors). In most neurons, activation of these receptors hyperpolarizes the cell membrane and inhibits neuronal signal transmission. Additionally, GABA also acts as a ligand for a G-protein couple receptor (GABA_B) that activates a subset of potassium ion channels, thus hyperpolarizing the cell membrane. Removal of GABA-ergic and glycinergic inhibition can lead to exaggerated nociceptive responses. For example, the inhibition of glycine release from interneurons (adenosine and nocistatin), a reduction (alteration) in transmembrane chloride gradient (reduced KCC2 cotransporter expression in damaged neurons), and the selective death of GABA-ergic/glycinergic interneurons are all possible mechanisms for development of neuropathic pain.

   Prostaglandins, in addition to their peripheral actions, can act centrally to enhance nociceptive transmission. Activation of intracellular phosphorylation pathways, for example the action of PGE2 on an EP2 receptor, initiates an intracellular pathway that activates protein kinase A (PKA). This effectively reduces inhibitory glycinergic transmission and results in centrally mediated sensitization.

   Many short- and longer-term changes in neuronal cell function underlie some pain mechanisms. Increases in the excitability of central nociceptive neurons can lead to their being activated by low levels of input from C or Aδ fibers (hyperalgesia). Changes in these central neurons can result in their being activated by Aβ fibers and can produce a situation where the stimulus they normally transduce (touch) now elicits a painful response. This is known as allodynia. Additionally, prostaglandins can induce transcriptional and posttranslational changes in normally non-nociceptive A-β fibers creating in them a nociceptive phenotype.

Opioids are widely used in the management of pain. They are often considered the first line of treatment for acute pain, particularly surgical pain. Opioids act on opioid receptors, which are found within the CNS and may be expressed or upregulated in peripheral tissues following trauma or inflammation. Different types of opioid receptors (μ or OP3, δ or OP1, κ or OP2) have been described, and commonly used drugs act on one or more of these receptor types.

   Individuals appear to be unique in terms of number, morphology, and distribution of opioid receptors, and these differences are genetically determined. It is not surprising, therefore, that some individuals experience much better pain relief from opioid agonists than others. Moreover, some human patients may not tolerate the side effects or may experience very different levels of pain relief with one drug versus an equianalgesic dose of another from the same class (e.g. full μ-agonists). Although these phenomena have not been reported in animals, consideration should be given to trying a different drug in the cases where unacceptable adverse effect or inadequate pain relief are obtained.

   Opioid analgesia is most effective for the treatment of acute pain; efficacy for chronic pain is variable. Most opioids produce dose-dependent sedation and have potential adverse effects, such as bradycardia, respiratory depression, vomiting, constipation, dysphoria, histamine release, hypothermia (dogs), hyperthermia (cats, drug-dependence), tachycardia (cats, high doses), and hypertension (cats, high doses). Adverse effects are usually mild if appropriate dose regimens are selected and bradycardia can be prevented or treated with anticholinergics. Clinically significant respiratory depression is rare in dogs and cats, except when using high doses of opioids, for example as part of a balanced anesthetic technique (during which mechanical ventilation should be provided). Vomiting is more common with morphine than other drugs. Histamine release is seen only with morphine and meperidine, and the speed and route of administration plays a role: a greater degree of histamine release occurs with fast versus slow administration and with the intravenous (IV) versus intramuscular (IM) or subcutaneous (SQ) routes. Opioid-induced dysphoria appears more common in cats and some dog breeds (e.g. Siberian Husky); however, true excitement (“morphine-mania”) in cats is rare and associated with the administration of excessively large doses.