Prospects for Further Studies?

16 May

NK1 receptor antagonists appear to reduce arthritic joint damage and resultant hypersensitivity in animals with adjuvant arthritis. There is high expression of NK1 receptor mRNA in synovia taken from patients with rheumatoid arthritis, and NK1 mRNA is positively correlated with serum C-reactive protein levels and radiological grade of joint destruction (Sakai et al. 1998), suggesting that NK1 receptor gene expression may reflect the disease progression in rheuma- toid arthritis. Achilles tendinosis is associated with sprouting of substance P- positive nerve fibres (Schubert et al. 2005). NK1 receptor antagonists may have potential for alleviating other bone-generated pain including bone cancer pain and fractures. A preclinical study using a murine  model of cancer pain has shown substantial internalisation of NK1 receptors on NK1 receptor-expressing neurons in lamina I of the spinal cord following non-noxious palpation of the tumourous  bone which was positively correlated with the extent of bone de- struction  (Schwei et al. 1999). In addition,  substance  P, acting via the NK1 receptor, stimulates osteoclast (OCL) formation  and activates OCL bone re- sorption (Goto et al. 2001). Since bisphosphonates and osteoprotegerin reduce tumour-induced bone pain by blocking bone resorption (Honore and Mantyh

2000), NK1 receptor  antagonists  could be effective in reducing bone cancer pain by blocking substance P-mediated bone resorption,  as well as the spinal

effects of substance P. Other chronic pain conditions in which NK1 receptor antagonists may be worth testing include fibromyalgia, a syndrome in which elevated levels of substance P are found in the cerebrospinal fluid (Russell et al.

1994). Recently, Littman et al. (1999) reported that the NK1 receptor antagonist CJ-11,974 (50 mg p.o. b.i.d. for 4 weeks) was able to reduce dysaesthesias in patients  with fibromyalgia, and in a subset of patients  there was some im- provement  in pain severity, morning stiffness and sleep disturbances.  These findings warrant further investigation.

The clinical trials published to date have focussed on somatic pains, and none has reported on the effects of NK1 receptor antagonists in visceral pain. The anatomical distribution of substance P certainly favours a major role in visceral rather than somatic pain as a greater number of visceral primary af- ferents (>80%) express substance  P compared  with only 25% in cutaneous afferents (Laird et al. 2001), and laminae I and X of the spinal dorsal horn, which receive afferents from the viscera, show the highest density of NK1 receptors  in  the  spinal  cord  (Li et al. 1998). It  has  recently  been  shown that  cardiac  somatic  nociception  involves NK1  receptor  activation  in  the parabrachial  complex (Boscan et al. 2005). The preclinical findings described above support a potential utility of NK1 receptor antagonists in visceral pain conditions.

The anomaly between data obtained in preclinical and clinical studies might be explained by species differences in physiology of substance P or distribution of NK1 receptors  or difference between clinical pain  and the responses  to noxious stimuli measured  in small animals. Whereas in rats substance  P is co-expressed in 5-HT dorsal raphe descending fibres (Neckers et al. 1979), in man it is restricted  to dorsal raphe ascending fibres (Sergeyev et al. 1999), suggesting that it may play a greater role in supraspinal  functions in man. It must be remembered that substance P is only one of many neurotransmitters expressed in primary sensory afferent neurons and that only a small proportion of these fibres (<25% of cutaneous fibres) contain substance P. Blocking the actions of substance P or NK1 receptors alone might not be sufficient to produce clinical analgesia. It is interesting  to note that animals injected intrathecally with saporin toxin conjugated to substance P to kill NK1 receptor-expressing cells within the dorsal horn, display a more pronounced anti-nociception than was achieved by blocking NK1 receptors (Mantyh et al. 1997; see also Morris et al. 2004) presumably by blocking all inputs to these neurons  and not just by inhibiting  the actions of substance P. Other studies have shown that the most important  action of substance  P might be to modulate  the action of other  transmitters in the spinal  cord, particularly  glutamate  (Juranek  and Lembeck 1997). Combination  of RP-67580 (but not its inactive enantiomer) with the N -methyl-d-aspartate (NMDA)/glycine receptor antagonist (+)-HA-

966 enhanced the anti-nociception in the rat formalin paw test (Seguin and Millan 1994). Similarly, Field and colleagues (2002) demonstrated a marked synergy of the anti-nociceptive effects of gabapentin when administered  with

the NK1 receptor  antagonists  CI-1021 or CP-99994 in neuropathic  (CCI or streptozotocin) rats.

In conclusion, although substance P, acting at NK1 receptors, appears to play an important role in pain transmission in animals, it is clear that NK1 receptor antagonists are not likely to be useable as simple analgesic drugs in the clinic although further clinical studies may be worthwhile. Some aspects of the action of substance P are hard to interpret and the clinical context is therefore obscure. It is noteworthy that the substance P locus of the preprotachykinin precursor

is needed for transport of δ-opioid receptors in primary afferents (Julius and

Basbaum 2005) and that substance P inhibits the production  of neuroactive

progesterone metabolites in spinal circuits (Patte-Mensah et al. 2005). NK1 re- ceptor neurotransmission has been suggested to have a role in the hyperalgesia following chronic morphine administration as a consequence of up-regulation of both substance P and NK1 receptor expression (King et al. 2005).



Evidence for a Role in Pain and Headache

Since its discovery in 1981 by Rosenfeld et al. (for review see Rosenfeld et al.

1992), CGRP has been shown to be an important neuropeptide that is widely distributed  in both  peripheral  and  central  nervous  systems (Hokfelt et al.

1992; Van Rossum et al. 1997). It is now known  to be one of a family of structurally related peptides comprising calcitonin, amylin, CGRPα and β plus adrenomedullin, which act at a characteristic group of GPCRs made up from multiple subunits (Poyner et al. 2002). For the purposes of this chapter most

attention  will be given to CGRP itself and the reader interested  in a general review of the properties of this peptide family and their role outside nociception is referred to Van Rossum et al. (1997).

CGRP is of particular interest in the context of nociception as it is the most abundant  peptide in primary afferent fibres and has the widest distribution across subtypes of primary afferents including myelinated fibres. It is present in virtually all substance P-containing  fibres and in many others (up to 80% of all primary afferents in the monkey; Hokfelt et al. 1992). Most of the CGRP immunoreactive  terminals  in the DHSC of the mouse are from primary  af- ferents, as rhizotomy produces a dramatic depletion although there is a small population  of CGRP mRNA positive cells in lamina III (Tie-Jun et al. 2001). There is a dense innervation  of the cat caudal trigeminal nucleus by CGRP- containing fibres which synapse with intrinsic neurons of the nucleus (Henry et al. 1993). CGRP-containing fibres also richly innervate the human trigeminal nucleus caudalis (Smith et al. 2002). Inflammation of the craniofacial muscle or

of the temporomandibular joint increases CGRP expression in the trigeminal ganglion and caudal trigeminal  nucleus (Ambalavanar et al. 2006; Hutchins et al. 2006). In the lumbar dorsal root ganglion (DRG) there is up-regulation of CGRP expression after inflammation  of the rat ankle (Hanesch et al. 1993). In collagen-induced  arthritis  in the rat (Nohr et al. 1999) or in an iodoac- etate model of osteoarthritis (Fernihough et al. 2005) there was also a marked increase in the DRG expression of CGRP. In streptozotocin  diabetic rats, in contrast, both CGRP and substance P expression were reduced several weeks after the induction of diabetes although an increase in mRNA in the DRG sug- gests this may have been associated with increased turnover  of the peptides (Troger et al. 1999). In a mouse fibrosarcoma  model of cancer pain it was found that hyperalgesic mice had tumours that were more densely innervated with CGRP immunoreactive  fibres and less vascularised than tumours  from non-hyperalgesic mice (Wacnik et al. 2005). The transforming  growth factor

(TGF)-β-related factor activin is released after damage or inflammation of pe- ripheral tissues and has been shown to increase CGRP expression in sensory

neurons and to produce tactile allodynia, leading to the suggestion that it may be the chemical mediator for this response (Xu et al. 2005). Partial sciatic nerve lesions in the rat produced increased expression of CGRP in those myelinated DRG neurons projecting to the gracile nucleus, again leading to the suggestion

that CGRP may be involved in the production  of tactile allodynia (Ma et al.

1999). Tumour necrosis factor (TNF)-α has been found to increase CGRP ex- pression in rat trigeminal ganglion neurons (Bowen et al. 2006) and in DRG

neurons (Opree and Kress 2000). The nociceptive acid sensing channel ASIC3 is co-localised with CGRP in trigeminal ganglion neurons retrogradely labelled from tooth pulp and facial skin (Ichikawa and Sugimoto 2002). Lumbar DRG

neurons in the mouse co-express CGRP and voltage-gated calcium channels of

N- and L-types (Just et al. 2001).

CGRP is distributed  widely but  unevenly across the CNS (Van Rossum et al. 1997). It has been found to co-exist with many other peptides; in mo- toneurons  it is found together  with VIP and somatostatin  in many species including human (Hokfelt et al. 1992).

Clinical association of CGRP signalling and somatic pain are limited, but it has recently been shown that mice with a heterozygous mutation of the Nf1 gene

(analogous to human neurofibromatosis type 1) exhibit increased sensitivity to noxious stimuli that correlates with increased CGRP release (Hingten et al.

2006), and human patients with this disorder have abnormal pain sensitivity. Studies in strains of mice selected on the basis of their differential sensitivity to noxious heat using both electrophysiological and behavioural assays indicate that the observed differences are linked to strain-dependent CGRP expression.

Linkage mapping suggests that a chromosome 7 polymorphism upstream of the Calca gene (coding CGRPα) is the cause of a heritable difference in both CGRP expression and noxious heat sensitivity (Mogil et al. 2005). The behavioural phenotype of mice in which the α-CGRP gene has been knocked out indicates

that CGRP is involved in neurogenic inflammation  and chemical nociception, but the full phenotype  of these mice is complex (Muff et al. 2004). There is elevated sympathetic nervous system activity (Oh-hashi et al. 2001) but overall there is normal  cardiovascular  regulation  and neuromuscular development

(Lu et al. 1999). The knock-out  protocol to deplete α-CGRP, however, leaves detectable amounts  of β-CGRP in DRG and spinal cord (Schutz et al. 2004).

It is relevant to note that the related peptide amylin is also found in primary afferent neurons in the mouse and rat, and knock-out mice lacking the amylin gene show reduced nociceptive responses in the formalin test (Gebre-Medhin et al. 1998). It has been reported  that amylin can be anti-nociceptive  when

injected into the cerebral ventricles, but this is almost certain to be due to an action at calcitonin receptors (Sibilia et al. 2000)

Perhaps the most persuasive clinical association is between CGRP and the

pathogenesis  of migraine headache (Edvinsson 2001; Brain et al. 2002). For example, intravenous  injection of CGRP induces a migraine-like headache in migraineurs  (Lassen et al. 2002), levels of CGRP are elevated in the external jugular vein during a migraine headache and following treatment with triptans the plasma levels of CGRP return  to control levels with successful ameliora- tion of the headache (Edvinsson and Goadsby 1995; Gallai et al. 1995). Plasma CGRP levels are higher than control in migraineurs  even between attacks of headache (Ashina et al. 2000) and a similar relationship has recently been ob- served in salivary CGRP, which is elevated in migraineurs, rises further during a headache and returns to control levels after effective treatment with a triptan (Bellamy et al. 2006). It is not completely clear as yet whether the importance of CGRP in migraine is because it is a neuronally released vasodilator (Limmroth et al. 2001), a nociceptive neurotransmitter or both. However, the vascular link is a persuasive one (see Edvinsson et al. 1995) and those areas of the brainstem  that have been suggested to be the migraine generator  have only sparse CGRP fibres in comparison with other neuropeptides (Tajti et al. 2001). Dural vasodilatation produced by i.v. CGRP in the rat produces a sensitisation of the responses of neurons  in the spinal trigeminal nucleus receiving input from low-threshold mechanoreceptors on the face (Cumberbatch  et al. 1999) although CGRP dural vessel dilation does not activate or sensitise meningeal nociceptors  (Levy et al. 2005). It is clear that cortical spreading  depression (which has been linked to migraine aura) does not produce CGRP release into the jugular vein blood in the way that trigeminal ganglion stimulation or the headache phase of migraine does (Piper et al. 1993; Edvinsson and Goadsby

1995). It is not possible to make a general association between CGRP and all headaches however and, for example, there is no correlation between the severe headache caused by pituitary tumours and CGRP (Levy et al. 2004).

Some limited data have been obtained using selective antibodies to sequester CGRP and neutralise its physiological effects. These have helped to confirm its importance in neurogenic vasodilatation (Tan et al. 1994, 1995) and in the

hyperalgesia following experimental arthritis (Kuraishi et al. 1988).

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