Peripheral Galanin Receptor 2 as a Target for the Modulation of Pain
Figure 1
Putative galanin-mediated neuronal pro- and antinociceptive mechanisms in the dorsal horn of the spinal cord. (a) In the naïve animal, GalR1 and GalR2 are expressed on the central terminals of a large proportion of small diameter TRPV1 expressing C fibres. Galanin itself is expressed at very low levels in a small number of neurons. Peripheral activation of nociceptive C fibre afferents leads to neurotransmitter release (e.g., glutamate) at the first synapse in the superficial dorsal horn in the spinal cord, including galanin release (filled circles) [46]. In the uninjured state, galanin release is low at this synapse. Evoked galanin release or exogenous galanin is postulated to activate presynaptic GalR2 (solid arrow). This stimulates signalling through in the central terminals, which then regulates both the sensitisation and expression of TRPV1 and hence afferent sensitivity [11, 47]. In addition, acts on type calcium channels [11], which would serve to enhance neurotransmitter release (e.g., glutamate, open circles), enhancing excitation of postsynaptic neurons. Postsynaptic neurons express both GalR1 and GalR2. GalR1 is expressed on both excitatory (glutamatergic) and inhibitory (GABA- and glycinergic) postsynaptic neurons, and activation reduces excitability of these neurons through actions on potassium channels (checkered boxes). Postsynaptic GalR2 activation is postulated to result in the low concentration pronociceptive effects of galanin [23]. The net effect of the activation of GalR1 and GalR2 on spinal nociceptive processing will differ depending on the degree of presynaptic activation and whether excitatory or inhibitory postsynaptic neurons are affected. GalR1 is also expressed on DRG neurons, but whether presynaptic effects of galanin are also mediated through GalR1 is not yet known as there is no evidence that these receptors are functional. Dashed lines indicate minimal effects on the pathways shown. (b) After nerve injury, galanin levels are massively upregulated in DRG neurons. Up to 50% of neurons now express galanin and to a much higher level, resulting in a 120-fold increase in DRG galanin expression. There is also a small increase in galanin expression in the dorsal horn, [13] where galanin is largely found in inhibitory neurons [48, 49]. Spontaneous firing increases in primary afferents, and galanin release into the dorsal horn is increased after both nerve injury [46] and nociceptor stimulation [46]. Spinal GalR levels are only minimally altered under these conditions. Increased galanin release into the dorsal horn would increase basal activation of presynaptic GalR2, which under high galanin concentrations couples to . TRPV1 sensitisation is therefore reduced. coupling also stops the activation of calcium channels thereby greatly reducing glutamate release and hence nociceptive input to the dorsal horn [25]. In addition, galanin exerts greater postsynaptic effects, effectively reducing central sensitisation [27, 44, 45]. In nerve injury, therefore, increased endogenous or exogenous galanin enhances these actions and results in antinociception. (c) (Inset) A schematic representation of the galanin concentration-dependent system. Pronociceptive actions are exerted by low-concentration galanin when GalR2 couples to . This then activates the protein kinase C-phospholipase C pathway to lead to enhanced nociceptor excitability and behavioural hypersensitivity. When galanin concentrations are higher, for example, after nerve injury, GalR2 couples to , reducing nociceptor excitability through inhibition of peripheral sensitisation.
