Immunohistochemical analysis of peptide pathways possibly related to pain and analgesia: enkephalin and substance P.

Abstract

The distribution of Met-enkephalin-and substance P-immunoreactive neurons was studied by indirect immunofluorescence in some areas related to pain and analgesia. Met-enkephalin-and substance P-positive cell bodies and nerve terminals were observed in the periaqueductal central gray, the nucleus raphe magnus, the marginal layer and substantia gelatinosa ofthe spinal trigeminal nucleus, and the dorsal horn of the spinal cord. Lesion experiments suggest that Met-enkephalin neurons in the dorsal horn and possibly in the spinal trigeminal nucleus are interneurons or propriospinal neurons with nerve terminals in the laminae I and II of tfe cord and in the superficial layers of the spinal trigeminal nucleus, respectively. These areas are also very rich in substance P-positive nerve terminals, mainly representing central branches of primary afferent neurons.The present immunohistochemical-anatomical findings support the hypothesis that stimulation-produced analgesia is related to activation of spinal and spinal trigeminal enkephalin interneurons forming axo-axonic synapses with (substance P?) pain afferents in the superficial laminae of the dorsal horn and the spinal trigeminal nucleus. These interneurons may be activated by sensory fibers and by descending fibers from medullary stimulation sites. Transmitter substances in these descending fibers may be 5-hydroxytryptamine and substance P. Morphine is a classical agent for the relief of severe, chronic pain. Strong analgesia can also be produced by electric stimulation of mesencephalic and medullary structures (refs. 1-9, see ref. 10), by acupuncture, or by "electroacupuncture" (11, 12), a modification of the classical Chinese procedure. Several observations suggest a common element in these approaches for pain relief. For instance, narcotic antagonists, such as naloxone (13), block analgesia induced by electrical stimulation (6)(7)(8)(9)14) and by morphine injections (15). Furthermore, tolerance develops to electrostimulation analgesia and to morphine analgesia and cross tolerance can be observed (16).Recently, Hughes and collaborators (17) have identified two pentapeptides, Leu-enkephalin and Met-enkephalin, that may represent endogenous ligands for opiate receptors. Available evidence suggests that the activity profile of endogenous opioids is similar to that of the opiates. For instance, enkephalin has analgesic activity in vivo and the narcotic antagonist naloxone will also counteract enkephalin-induced elevation of pain thresholds (18,19). It is therefore conceivable that these ligands may be involved in stimulation-produced analgesia.Using the immunohistochemical approach, we have been able to outline the gross distribution of enkephalin-positive structures in the central nervous system (refs. 20 and 21, see also ref. 22). Enkephalin neurons were found in many areas of the brain and spinal cord, indicating involvement in many different types of central nervous system functions. Here, however, we focus attention strictly on areas assumed to be of importa...

Immunoreactivity of NOS, CGRP, PACAP, SP and VIP in the trigeminal nucleus caudalis and in the cervical spinal cord C1 and C2 of the cat

“…NOS and PACAP immunoreactivities were moderate in these areas while only occasional VIP-positive fibers were seen. This distribution of CGRP, SP and VIP immunoreactivity corresponds well with the pattern seen in earlier studies of other animals [17][18][19][20]. A similar pattern of NOS-positive nerve fibers has been described in the dorsal horn of the cat spinal cord [21][22][23].…”

Substance P as a Transmitter Candidate

“…In the dorsal horn, met-enkephalin-positive cell bodies and nerve terminals are in close proximity to SP-positive cell bodies and nerve terminals; lesion experiments suggest that these neurons are interneurons (Hokfelt et al 1977d). Results from a number of studies suggest that opiates and enkephalin act on the primary afferent terminals and fi bers.…”

Naloxone modulates the perception of itch in man [letter]

“…Both itch and pain are transmitted to the dorsal horns of the spinal cord by small diameter (c) fibres (Zotterman, 1939), and are probably integrated at a common site at each spinal segment (Graham, Goodell & Wolff, 1951). Furthermore, there is evidence that pain may be modulated by an enkephalin system in the interneurones of the substantia gelatinosa in each dorsal horn (Hokfelt, Ljungdahl, Terenius, Elde & Nilsson, 1977;Jessell & Iversen, 1977). In these experiments the effect of naloxone on nocturnal itch was studied in patients with cholestatic liver disease who had severe protracted itching.…”