Spinal Substance P Receptor Expression and Internalization in Acute, Short-Term, and Long-Term Inflammatory Pain States

Abstract

Inflammatory pain involves the sensitization of both primary afferent and spinal cord neurons. To explore the neurochemical changes that contribute to inflammatory pain, we have examined the expression and ligand-induced internalization of the substance P receptor (SPR) in the spinal cord in acute, short-term, and long-term inflammatory pain states. These inflammatory models included unilateral injection of formalin (8-60 min), carrageenan (3 hr), and complete Freund's adjuvant (CFA; 3 d) into the rat hindpaw as well as adjuvant-induced polyarthritis (21 d). In acute inflammatory pain there is ongoing release of substance P (SP) as measured by SPR internalization in lamina I neurons at both 8 and 60 min after formalin injection. Although there is no tonic release of SP in short-term inflammatory pain, at 3 hr after carrageenan injection, SP is released in response to both noxious and non-noxious somatosensory stimulation with SPR internalization being observed in neurons located in both laminae I and III-IV. In long-term inflammatory pain models (CFA and polyarthritis) the same pattern of SP release and SPR activation occurs as is observed in short-term inflammation with the addition that there is a significant upregulation of the SPR in lamina I neurons. These results suggest that SPR internalization might serve as a marker of the contribution of ongoing primary afferent input in acute and persistent pain states. These stereotypical neurochemical changes suggest that there are unique neurochemical signatures for acute, short-term, and long-term inflammatory pain.

Effect of peptidases on the ability of exogenous and endogenous neurokinins to produce neurokinin 1 receptor internalization in the rat spinal cord

“…The amount of NK1R internalization was quantified using a standard method (Mantyh et al, 1995;Abbadie et al, 1997;Honore et al, 1999;Schwei et al, 1999;Trafton et al, 1999; with minor modifications (Marvizon et al, 1997;1999a). Briefly, we determined the percentage of NK1R immunoreactive neurons in lamina I that show internalization in relation to the total number of NK1R neurons sampled.…”

“…In contrast, we show here that inhibitors of NEN and DEC produced a relatively smaller increase (2.8 -3.5 times) in the potencies of SP and NKA to produce NK1R internalization. Moreover, whereas peptidase inhibitors are required to observe m-opioid receptor internalization in dorsal horn neurons produced by endogenously released opioids (Song & Marvizon, 2003), endogenously released neurokinins produce abundant NK1R internalization in the absence of peptidase inhibitors (Mantyh et al, 1995;Allen et al, 1997;Liu et al, 1997;Marvizon et al, 1997;1999a;Cao et al, 1998;Honore et al, 1999;Riley et al, 2001). Therefore, it is possible to use peptidase inhibitors to enhance the analgesic effect of endogenous opioids (Noble et al, 1992b;Roques, 2000) without increasing NK1R activation by endogenous neurokinins.…”

“…NK1R activation was measured by their internalization, a technique validated in numerous studies (Mantyh et al, 1995;Allen et al, 1997;Liu et al, 1997;Marvizon et al, 1997;1999a;Cao et al, 1998;Honore et al, 1999;Riley et al, 2001). An additional goal of this study was to compare the potencies of SP, NKA and NKB to produce NK1R internalization.…”

Cloning of Human Preprotachykinin-I Promoter and the Role of Cyclic Adenosine 5′-Monophosphate Response Elements in Its Expression by IL-1 and Stem Cell Factor

“…The role of PPT-I in hemopoiesis and angiogenesis, and its overexpression in breast and other cancers that metastasize to the bone marrow (BM), suggest that PPT-I could have a central role in BM metastasis (4 -6). PPT-I is also associated with pain, asthma, arthritis, aggressive behavior, and depression (1,(7)(8)(9). The evolutionary conserved sequence of PPT-I peptides underscores the importance of the pleiotropism that they demonstrate in interactive biological functions (10).…”

Noxious mechanical stimulation evokes the segmental release of opioid peptides that induce μ-opioid receptor internalization in the presence of peptidase inhibitors

“…This approach provides an ideal way to locate the areas of opioid release, because MORs serve as opioid detectors located in close proximity to opioid-releasing terminals and able to detect all naturally-occurring MOR agonists (Song and Marvizon, 2003a). Previously, neurokinin 1 receptor (NK1R) internalization had been used to measure substance P release (Abbadie et al, 1997;Allen et al, 1997;Honore et al, 1999;Kondo et al, 2005;Mantyh et al, 1995;Marvizon et al, 1997;Marvizon et al, 2003). Importantly, the magnitude of NK1R internalization increased with the intensity of the stimulus used to evoke substance P release, both when a noxious stimulus was used in vivo (Allen et al, 1997), or a chemical stimulus in vitro .…”