The authors have declared that no competing interests exist.
Substance P is released in painful and inflammatory conditions, affecting both peripheral processes and the central nervous system neurokinin 1 (NK1) receptor. There is a paucity of data on human brain alterations in NK1 expression, how this system may be affected by treatment, and interactions between central and peripheral tissue alterations. Ten subjects with chronic tennis elbow (lateral epicondylosis) were selected out of a larger (n = 120) randomized controlled trial evaluating graded exercise as a treatment for chronic tennis elbow (lateral epicondylosis). These ten subjects were examined by positron emission tomography (PET) with the NK1-specific radioligand 11C-GR205171 before, and eight patients were followed up after treatment with graded exercise. Brain binding in the ten patients before treatment, reflecting NK1-receptor availability (NK1-RA), was compared to that of 18 healthy subjects and, longitudinally, to the eight of the original ten patients that agreed to a second PET examination after treatment. Before treatment, patients had significantly lower NK1-RA in the insula, vmPFC, postcentral gyrus, anterior cingulate, caudate, putamen, amygdala and the midbrain but not the thalamus and cerebellum, with the largest difference in the insula contralateral to the injured elbow. No significant correlations between brain NK1-RA and pain, functional severity, or peripheral NK1-RA in the affected limb were observed. In the eight patients examined after treatment, pain ratings decreased in everyone, but there were no significant changes in NK1-RA. These findings indicate a role for the substance P (SP) / NK1 receptor system in musculoskeletal pain and tissue healing. As neither clinical parameters nor successful treatment response was reflected in brain NK1-RA after treatment, this may reflect the diverse function of the SP/NK1 system in CNS and peripheral tissue, or a change too small or slow to capture over the three-month treatment.
Pain from the tendons that join the forearm muscles on the outside of the elbow, i.e. tennis elbow (TE) or lateral epicondylitis, has a prevalence of 1–3% in the population [
The study sample was part of a larger randomized controlled trial, evaluating graded exercise as a treatment for chronic TE, see [
The diagnosis was verified by pain on palpation, stretching (Mill´s test), loading and Maudsley´s middle finger test by a general practitioner and pain specialist (MP). 120 subjects were included in the larger randomized controlled trial (RCT), and each subject recruited in the RCT was invited to participate in the PET study, until ten accepted. The RCT is registered as NCT00888225 at
For a detailed description of study participants, we refer to [
Metric | n or mean | (SD) or % | |
---|---|---|---|
Number of participants | 10 | ||
Age, years | 48.7 | (8.5) | |
Women | 5 | 50% | |
Educational level | |||
Compulsory education only | 2 | 20% | |
Vocational training | 4 | 40% | |
Upper secondary school | 1 | 10% | |
College or university | 3 | 3% | |
Marital status | |||
Never married | 1 | 10% | |
Married or cohabiting | 9 | 90% | |
Smoking habits | |||
Never smoked | 5 | 50% | |
Ex-smokers | 3 | 30% | |
Current smokers | 2 | 20% | |
Duration of present epicondylosis, weeks | 52.0 | (42.9) | |
Previous treatments given | |||
NSAID | 4 | 40% | |
Acupuncture | 4 | 40% | |
Steroid injections | 3 | 30% | |
Stretching | 4 | 40% | |
Orthosis or other fixative | 3 | 30% | |
Massage | 1 | 10% | |
Rest | 1 | 10% | |
No previous treatment | 1 | 10% | |
VAS 0–100 Pain ratings | |||
Unaffected elbow pre-treatment, n = 10 | 5 | (2) | |
Affected elbow pre-treatment, n = 10 | 58 | (10) |
|
Unaffected elbow post-treatment, n = 8 | 4 | (2) | |
Affected elbow post-treatment, n = 8 | 25 | (21) |
n = number of participants, SD = Standard Deviation, NSAID = Nonsteroidal anti-inflammatory drug, VAS = Visual Analog Scale.
* Significantly higher pain ratings in affected elbow, paired t-test p<0.001.
** Significant reduction of pain after treatment, paired t-test, p = 0.001.
In addition, eighteen healthy, pain-free control subjects (9 females, 9 males, age 35 ± 9 years) were recruited through advertisements. Data from this control group have previously been reported in [
All subjects, except one, had right lateralized TE. Treatment consisted of a three-month daily exercise regime performed at home, with gradually increasing load on the extensor muscles of the affected forearm, see [
The PET examinations were performed twice in eight of the ten patients, before and after the treatment protocol of the RCT. Two patients declined a second PET examination after treatment and thus only participated once in the PET examination. PET examinations were performed only once in the healthy controls.
The NK1-specific radioligand 11C-GR205171, synthesized according to standard manufacturing procedures [
Fig adapted from [
For brain imaging, a 10 min transmission scan was performed using three retractable 68Ge rotating line sources. Thereafter, a bolus of approximately 5.2 MBq/kg bodyweight (average dose 400 ± 13 MBq), diluted in saline, total volume 5 ml was injected into the dorsal vein of the right foot, and 14 frames of dynamic data with progressively increasing duration (4 × 60 s, 3 × 120 s, 7 × 300 s), in total 45 min, were collected in 3D mode starting at the time of bolus injection. After the brain scan, the patients were moved and a 10-minute frame was collected over the elbow joints [
Dynamic 11C-GR205171 PET frames were realigned within scans to adjust for movements during scanning. Parametric PET images were generated using the Patlak reference tissue model [
All except one subject had right-sided TE. It can be assumed that unilateral chronic pain mostly affects the contralateral hemisphere; thus, the brain data of the one patient with left TE was flipped in the left-right direction to homogenize the data with regards to laterality, as has been done in other clinical pain studies [
The average NK1-RA values from all voxels included in the ROIs were extracted and t-tests were performed between healthy subjects and controls, between left and right hemispheres within the patient group, and finally within patients pre- and post-treatment. With a total of 21 ROI´s, the Bonferroni corrected P value of 0.05 was set at p<0.0024.
In addition to ROI analyses, NK1-RA differences between patients and controls were analyzed on a voxel by voxel basis using statistical parametrical mapping (SPM8) in a general linear model (GLM) with age and gender as nuisance variables. In four separate SPM8 GLM regression models, we further explored potential correlations between central NK1 receptor alterations and
NK1-RA alterations after treatment were evaluated in the 8 available patients in a ROI analysis with paired t-test, and in a whole brain GLM with paired t-tests. Moreover, treatment-induced changes in pain ratings and in peripheral uptake of 11C-GR205171 were evaluated in relation to treatment-induced changes in CNS uptake of 11C-GR205171.
Pain was rated on a 100 mm visual analogue scale (VAS), during maximum voluntary contraction of the forearm extensor muscles. Patients rated their pain in the affected arm an average 58 (±10) and in the unaffected arm an average of 5 (±2), before treatment (p<0.0001). After treatment, patients rated their pain in the affected arm an average of 25 (treatment effect p = 0.007). Treatment also led to a significant reduction in disability (DASH change = 11 points, p = 0.001).
Seven of the eight subjects had substantial (39–96%) reductions in VAS ratings after treatment, while one subject essentially rated pain the same before and after treatment (VASpre = 68, VASpost = 67).
Before treatment, patients had significantly lower NK1-RA in most ROIs (insula, vmPFC, right postcentral gyrus, anterior cingulate, right caudate, putamen, amygdala and the midbrain). There were no group differences in the thalamus. With regards to the control regions, there were no group differences in the cerebellum (Patlak reference region with no NK1 receptors), but both whole brain and primary visual cortex NK1-RA were significantly lower in the patient group, see
(n = 18, in blue), patients pre-treatment (n = 10, in red) and patients post-treatment (n = 8, in green).
Average NK1-RA (Normalized Patlak Slope Values) in Regions of Interest. HC vs. Pat Indicates t-test Between 18 Healthy Controls and 10 Patients with Chronic Tennis Elbow. Patpre vs. Patpost Indicates Paired t-tests in 8 Patients Examined Before (Pre) and After (Post) a Three-months Treatment Program of Daily Exercise.
ROI | Healthy (stdev) | Patients Pre | Patients post | HC vs. Pat | Patpre vs. Patpost |
---|---|---|---|---|---|
L Insula | 76.5(6.8) | 63.3(9.2) | 61.9(7.4) | 0.00020 |
0.14 |
R Insula | 77.4 (6.7) | 64.9(8.3) | 60.8(11.7) | 0.00019 |
0.12 |
L vmPFC | 71.4(5.7) | 61.0(4.8) | 59.2(9.3) | 0.000042 |
0.54 |
R vmPFC | 74.6(8.4) | 61.1(6.7) | 56.5(12.7) | 0.00018 |
0.13 |
L Postcentral | 73.5(7.2) | 64.5(6.3) | 62.1(7.4) | 0.0028 | 0.045 |
R Postcentral | 74.0(6.9) | 64.5(5.7) | 61.2(7.1) | 0.0011 |
0.057 |
L ACC | 70.4(6.7) | 60.8(6.8) | 53.9(13.3) | 0.0014 |
0.18 |
R ACC | 71.5(8.8) | 57.0(9.1) | 57.3(9.4) | 0.00035 |
0.24 |
L Thalamus | 58.4(10.3) | 51.8(9.5) | 53.8(11.9) | 0.11 | 0.93 |
R Thalamus | 58.5(12.8) | 51.2(8.7) | 51.5(10.7) | 0.12 | 0.58 |
L Caudate | 72.6(14.0) | 62.5(7.7) | 61.3(6.6) | 0.045 | 0.39 |
R Caudate | 71.5(9.4) | 59.0(8.3) | 57.4(7.0) | 0.0017 |
0.070 |
L Putamen | 107.4(11.0) | 86.2(11.0) | 85.4(6.4) | 0.000046 |
0.42 |
R Putamen | 105.7(10.7) | 86.4(8.3) | 85.4(9.9) | 0.000042 |
0.45 |
L Amygdala | 68.0(7.3) | 58.3(5.2) | 56.5(10.8) | 0.0011 |
0.52 |
R Amygdala | 70.6(8.7) | 55.9(5.0) | 56.7(7.0) | 0.000049 |
0.94 |
Midbrain | 107.4(11.0) | 86.2(11.0) | 85.4(6.4) | 0.000046 |
0.42 |
Whole Brain | 71.2(6.6) | 60.5(5.7) | 58.4(7.1) | 0.00021 |
0.090 |
Primary visual | 88.4(10.0) | 72.2(11.0) | 70.9(6.3) | 0.00050 |
0.26 |
L Cerebellum | 6.2(2.3) | 7.2(2.3) | 7.1(4.8) | 0.26 | 0.92 |
R Cerebellum | 7.6(2.4) | 8.4(3.1) | 7.1(4.4) | 0.45 | 0.47 |
L left, R Right, vmPFC ventromedial Prefronal Cortex, ACC Anterior Cingulate Cortex
* Significant at p<0.0024 (Bonferroini corrected p<0.05)
The voxelwise SPM analysis indicated that the most pronounced NK1-RA alterations (i.e. lower NK1-RA in patients) occurred in the posterior insula, contralateral to the injured elbow, see
The color bar indicates t-values. The background image is the average Patlak-slope value of all patients and controls (note the absence of NK1-receptors in the cerebellum).
Significant Reductions in NK1-RA in the Patient Group as Contrasted to the Healthy Control Group when Controlled for Age and Gender.
Region | Cluster size | Peak PFWE | T-value | MNIX,Y,Z |
---|---|---|---|---|
Left Insula | 61 | 0.019 | 5.2 | -36, -18, 5 |
Right ParaHippocampal Gyrus | 141 | 0.001 | 4.91 | 30, 2, -37 |
(Right Middle Temporal Pole) | 4.6 | (42, 4, -27) | ||
(Right Fusiform Gyrus) | 3.71 | (36, -6, -37) | ||
Left Superior Temporal Pole | 160 | 0.001 | 4.86 | -28, 8, -25 |
Left Superior Occipital Gyrus | 44 | 0.041 | 4.54 | -24, -78, 37 |
Left Superior Temporal Gyrus | 67 | 0.015 | 4.5 | -50, -44, 13 |
Left Hippocampus | 51 | 0.029 | 4.43 | -12–4–13 |
(Left Putamen) | 3.95 | (-20, 6, -5) | ||
Right Superior Temporal Gyrus | 63 | 0.017 | 4.31 | 70, -44, 23 |
(Right Supramarginal Gurus) | 3.92 | (70, -48, 33) |
Cluster subpeaks are indicated in parenthesis, labelling based on AAL-library. FWE family wise error corrected p value.
11C-GR205171 time radioactivity curves were similar in the cerebellum region, and decreased in patients across cortical and subcortical regions, see
X-axis is in seconds; y- axis is Standardized Uptake Values (normalized for dose and weight).
In seven out of the eight subjects examined after treatment, pain ratings decreased substantially (39 to 96%), but there were no significant changes in NK1-RA after treatment, either in the ROI analysis or in the SPM analysis. Furthermore, there were no significant correlations between changes in CNS NK1-RA and changes in pain ratings or peripheral tracer uptake.
We observed a general reduction of NK1-RA throughout the CNS in patients with chronic tennis elbow. This is in line with previous human studies on whiplash associated disorder [
In an animal model with voluntary, highly repetitive, negligible force reaching task—similar to that of a tennis elbow repetition injury—SP levels and spinal cord NK1 receptor expression was up-regulated in the superficial lamina of spinal cord dorsal horns at 6 and 10 weeks. [
Of note, the included patients all displayed peripherally elevated uptake of 11C-GR205171 in the affected arm [
The findings of this study suggest a role for the NK1 receptor in the CNS in a chronic, soft tissue-related pain condition such as chronic TE. The observed lower NK1 receptor availability in patients is interpreted as reflecting elevated endogenous SP levels creating receptor occupancy, desensitization and internalization, NK1 receptor downregulation, or a combination between these mechanisms. The CNS alterations were not specific to pain processing regions, and no effects of a three-month successful treatment program were observed, suggesting that the alterations are neither specific nor directly reflect the perception of pain.