Introduction
The neural circuits that are responsible for pain and the reactions to pain can be termed the pain system or, perhaps more appropriately, the pain systems . The pain systems include (1) peripheral neurons with a set of peripheral receptive elements, the nociceptors; (2) numerous central neuronal relay pathways; and (3) sets of integrative neurons that impose excitatory or inhibitory influences on nociceptive information at numerous levels of the neuraxis.
The initial reception of input perceived to be painful occurs on the peripheral terminations of nociceptors transducing noxious mechanical, temperature, and chemical stimuli. Nociceptors transmit information about internal or external stimuli that are noxious, distressing, or damaging to second-order neurons located in the spinal cord or brainstem level innervated (i.e., the lumbar spinal cord for leg input, the thoracic spinal cord for stomach lining input, and the trigeminal spinal nucleus for face input). Nociceptive signals are then transmitted by projection neurons of the pain system to integration sites in the brainstem. A primary integration site for sensory information is the thalamus, but numerous other brainstem and higher brain structures are participants in the integrative neuronal circuits responding to pain.
A variety of coordinated pain reactions are generated, including protective somatic and autonomic reflexes, endocrine actions, emotional responses, learning and memory about the event, and cortical awareness of pain. In addition to pain transmission and pain reactions, the brain centers that receive nociceptive information also provide either negative or positive feedback that reduces or accentuates pain and pain reactions. Negative feedback to the spinal cord circuitry is mediated by descending pathways that are often called the “endogenous analgesia system.” The mechanism and pathways responsible for accentuation of pain and pain reactions, referred to as central sensitization or facilitation, can involve increased responsiveness at all levels of the pain system, including the peripheral nociceptors, spinal cord, brainstem, and higher centers. The net effect of the positive and negative alterations in circuitry leads to the perceptual experience of “pain.”
Nociceptors
Peripheral Receptive Elements
The initial reception of noxious input perceived to be painful occurs at the specialized endings of primary afferent sensory neurons known as nociceptors. Reception of noxious input occurs in functionally specialized free nerve endings of the skin, muscle, joints, viscera, and dura ( Fig. 8.1 ). Nociceptive endings are also located in the fascia and adventitia of blood vessels. Glutamate receptors, as well as µ- and δ-opiates, substance P (SP), somatostatin, and vanilloid receptors, have been identified immunohistochemically on the peripheral endings of cutaneous nerve fibers. Nociceptor subtypes respond best to either mechanical (mechanical nociceptors), mechanical and thermal (mechanothermal nociceptors), or mechanical, thermal, and chemical stimuli (polymodal nociceptors). Common types of cutaneous nociceptors are Aδ mechanoreceptors and C polymodal nociceptors, which relay the transduced information about potentially harmful input via Aδ and C fibers, respectively.
Peripheral Nerves
The axons that relay information about noxious input from the skin and other tissues to the central nervous system (CNS) fall characteristically into the range of small, unmyelinated axonal fibers with conduction velocities lower than 2.5 m/sec for C fiber (or group IV) nociceptors ( Fig. 8.2 ) and small fibers wrapped in a thin layer of myelin produced by Schwann cells with a conduction velocity of 4 to 30 m/sec in the case of Aδ fibers (or group III). Primary afferent C fibers are more numerous than myelinated primary afferents in peripheral nerves. For example, in dorsal roots, the ratio of C fibers to A fibers is about 2.5:1, and in joint nerves (after sympathetic postganglionic axons are removed by sympathectomy), the ratio of C to A fibers is 2.3:1.
